Aromatic amine derivatives having NOS inhibiting action

ABSTRACT

Compounds represented by the general formula (1):                    
     (where R 1  and R 2  are typically a hydrogen atom; R 3  and R 4  are typically a hydrogen atom or a lower alkyl group; R 5  is typically a hydrogen atom; X 1 , X 2 , X 3  and X 4  are typically a hydrogen atom or a lower alkoxy group; A is typically an optionally substituted pyridine ring; m and n are each 0 or 1) have an NOS inhibiting activity and are useful as therapeutics of cerebrovascular diseases and other pharmaceuticals.

CROSS REFERENCE TO RELATED APPLICATION

The present application is the national stage under 35 U.S.C. 371 of PCT/JP97/04762, filed Dec. 24, 1997.

TECHNICAL FIELD

This invention relates to N-substituted aniline derivatives, more particularly to compounds represented by the general formula (I) that have a nitric oxide synthase (NOS) inhibiting action to suppress the production of nitric oxide (NO) and thereby prove effective against disorders and diseases in which excessive NO or NO metabolites are supposedly involved, namely, cerebrovascular diseases [cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction (atherothromobotic infarction, lacunar infarction and cardiogenic embolism), transient ischemic attack and cerebral edema], traumatic brain injury, spinal injury, pains [headache (migraine, tension headache, cluster headache and chronic paroxysmal headache)], Parkinson's disease, Alzheimer's disease, seizure, morphine tolerance or dependence, septic shock, chronic rheumatoid arthritis, osteoarthritis, viral or nonviral infections and diabetes mellitus. The invention also relates to possible tautomers, stereoisomers and optically active forms of said compounds, as well as pharmaceutically acceptable salts thereof. The invention further relates to preventives and therapeutics that contain said compounds, derivatives or pharmaceutically acceptable salts as active ingredients.

BACKGROUND ART

The number of deaths from cerebrovascular diseases in Japan had increased until 1970 when it began to decline mostly due to the improvement in their acute-phase therapy. Nevertheless, cerebrovascular diseases remain the second leading cause of death among adult diseases, next only to cancers. As for the incidence of cerebrovascular diseases, many statistical surveys indicate that it is generally constant and in view of the fact that the number of elderly persons will increase at an uncomparably faster speed in Japan than any other country in the world, the number of patients suffering from cerebrovascular diseases is estimated to increase rather than decrease in the future. The declining mortality and the growing population of aged people combine to increase the cases of cerebrovascular diseases in the chronic phase and this has presented with a national problem not only from the aspects of individual patients and society at large but also from the viewpoint of medical economics since patients with chronic cerebrovascular disease are inevitably involved in long-term care. In cerebral infarction that accounts for most cases of cerebrovascular diseases, cerebral arteries are occluded and blood deficit starting at the blocked site extends to the peripheral site, causing an ischemic state. The symptoms of cerebral infarction in the chronic phase are in almost all cases derived from the loss of neurons and it would be extremely difficult to develop medications or established therapeutic methods for achieving complete recovery from those symptoms. Therefore, it is no exaggeration that the improvement in the performance of treatments for cerebral infarction depends on how patients in an acute phase can be treated with a specific view to protecting neurons and how far their symptoms can be ameliorated in the acute phase. However, most of the medications currently in clinical use are antiplatelet drugs, anticoagulants and thrombolytics and none of these have a direct nerve protecting action (see Kazuo MINEMATSU et al., “MEDICINA”, published by Igaku Shoin, 32, 1995 and Hidehiro MIZUSAWA et al., published by Nankodo, “Naika” 79, 1997). Therefore, it is desired to develop a drug that provides an effective therapy for cerebrovascular diseases, in particular cerebral infarction, by working in an entirely novel and different mechanism of action from the conventional medications.

A presently dominant theory based on genetic DNA analyses holds that NOS exists in at least three isoforms, namely, calcium-dependent nNOS (type 1) which is present constitutively in neurons, calcium-dependent eNOS (type 3) which is present constitutively in vascular endothelial cells, and apparently calcium-independent iNOS (type 2) which is induced and synthesized by stimulation with cytokines and/or lipopolysaccharides (LPS) in macrophages and many other cells (Nathan et al., FASEB J. 16, 3051-3064, 1992; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).

A mechanism that has been proposed as being most probable for explaining the brain tissue damage which accompanies cerebral ischemia is a pathway comprising the sequence of elevation in the extracellular glutamic acid level, hyperactivation of glutamic acid receptors on the post-synapses, elevation in the intracellular calcium level and activation of calcium-dependent enzymes (Siesjö, J. Cereb. Blood Flow Metab. 1, 155-185, 1981; Siesjö, J. Neurosurg. 60, 883-908, 1984; Choi, Trends Neurosci. 11, 465-469, 1988; Siesjö and Bengstsson, J. Cereb. Blood Flow Metab. 9, 127-140, 1989). As already mentioned, nNOS is calcium-dependent, so the inhibition of hyperactivation of this type of NOS isoforms would contribute to the neuro-protective effects of NOS inhibitors (Dawson et al., Annals Neurol. 32, 297-311, 1992).

As a matter of fact, the mRNA level of nNOS and the number of nNOS containing neurons start to increase early after focal cerebral ischemia in rats and their temporal alterations coincide with the development of infarction (Zhang et al., Brain Res. 654, 85-95, 1994). In addition, in a mouse model of focal cerebral ischemia, the percent inhibition of nNOS activity and the percent reduction of infarct volume correlate to each other at least in a dose range of N^(G)-nitro-L-arginine (L-NA) that produces a recognizable infarct volume reductive action (Carreau et al., Eur. J. Pharmacol. 256, 241-249, 1994). Further in addition, it has been reported that in nNOS knockout mice, the infarct volume observed after focal cerebral ischemia is significantly smaller than that in the control (Huang et al., Science 265, 1883-1885, 1994).

Referring now to NO, it is at least one of the essences of endothelium-derived relaxing factor (EDRF) and, hence, is believed to take part in the adjustment of the tension of blood vessels and the blood flow (Moncade et al., Pharmacol. Rev. 43, 109-142, 1991). As a matter of fact, it was reported that when rats were administered high doses of L-NA, the cerebral blood flow was found to decrease in a dose-dependent manner as the blood pressure increased (Toru MATSUI et al., Jikken Igaku, 11, 55-60, 1993). The brain has a mechanism by which the cerebral blood flow is maintained at a constant level notwithstanding the variations of blood pressure over a specified range (which is commonly referred to as “autoregulation mechanism”) (“NOSOTCHU JIKKEN HANDBOOK”, complied by Keiji SANO, published by IPC, 247-249, 1990). The report of Matsui et al. suggests the failure of this “autoregulation mechanism” to operate. Therefore, if eNOS is particularly inhibited beyond a certain limit in an episode of brain ischemia, the cerebral blood flow will decrease and the blood pressure will increase, thereby aggravating the dynamics of microcirculation, possibly leading to an expansion of the ischemic lesion. It was also reported that in eNOS knockout mice, the infarct observed after focal cerebral ischemia was larger than that in the control but could be reduced significantly by administration of L-NA (Huang et al., J. Cereb. Blood Flow Metab. 16, 981-987, 1996). These reports show that eNOS-derived NO probably works protectively on the brain tissue through the intermediary of a vasodilating action, a platelet aggregation suppressing action and so forth.

The present inventors previously found that L-NA, already known to be a NOS inhibitor, possessed ameliorative effects on the brain edema and cerebral infarction following phenomena that developed after experimental cerebral ischemia (Nagafuji et al., Neurosci. Lett. 147, 159-162, 1992; Japanese Patent Public Disclosure No. 192080/1994), as well as necrotic neuronal cell death (Nagafuji et al., Eur. J. Pharmacol. Env. Tox. 248, 325-328, 1993). On the other hand, relatively high doses of NOS inhibitors have been reported to be entirely ineffective against ischemic brain damage and sometimes aggravating it (Idadecola et al., J. Cereb. Blood Flow Metab. 14, 175-192, 1994; Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku, 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995). It should, however, be stressed that as a matter of fact, all papers that reported the changes of NO or NO-related metabolites in the brain and blood in permanent or temporary cerebral ischemic models agreed in their results to show the increase in the levels of those substances (Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku, 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).

One of the reasons for explaining the fact that conflicting reports have been made about the effectiveness of NOS inhibitors in cerebral ischemic models would be the low selectivity of the employed NOS inhibitors for nNOS. As a matter of fact, no existing NOS inhibitors including L-NA and N^(G)-nitro-L-arginine methyl ester (L-NAME) have a highly selective inhibitory effect on a specific NOS isoform (Nagafuji et al. Neuroreport 6, 1541-1545, 1995; Nagafuji et al. Mol. Chem. Neuropathol. 26, 107-157, 1995). Therefore, it may well be concluded that desirable therapeutics of ischemic cerebrovascular diseases should have a selective inhibitory effect on nNOS (Nowicki et al., Eur. J. Pharmacol. 204, 339-340, 1991; Dawson et al., Proc. Natl. Acad. Sci. USA 88, 6368-6371, 1991; Iadecola et al., J. Cereb. Blood Flow Metab. 15, 52-59, 1995; Iadecola et al., J. Cereb. Blood Flow Metab. 15, 378-384, 1995; Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).

It has also been suggested that nNOS inhibitors have the potential for use as therapeutics of traumatic brain injuries (Oury et al., J. Biol. Chem. 268, 15394-15398, 1993; MacKenzie et al., Neuroreport 6, 1789-1794, 1995; Mesenge et al., J. Neurotrauma. 13, 11-16, 1996; Wallis et al., Brain Res., 710, 169-177, 1996), headache and other pains (Moore et al., Br. J. Pharmacol. 102, 198-202, 1991; Olesen., Trends Pharmacol. 15, 149-153, 1994), Parkinson's disease (Youdim et al., Advances Neurol. 60, 259-266, 1993; Schulz et al., J. Neurochem. 64, 936-939, 1995; Hantraye et al., Nature Medicine 2, 1017-1021, 1996), Alzheimer's disease (Hu and EI-FaKahany, Neuroreport 4, 760-762, 1993 Meda et al., Nature 374, 647-650, 1995), seizure (Rigaud-Monnet et al., J. Cereb. Blood Flow Metab. 14, 581-590, 1994), and morphine tolerance and dependence (Kolesnikov et al., Eur. J. Pharmacol. 221, 399-400, 1992; Cappendijk et al., Neurosci. Lett. 162, 97-100, 1993).

Upon stimulation by certain kinds of cytokines and/or LPS, iNOS is induced in immunocytes such as macrophages and glial cells and other cells, and the resulting large amount of NO will dilate blood vessels to cause a fatal drop in blood pressure. Therefore, it is speculated that an iNOS inhibitor may be effective against septic shocks (Kilbourn and Griffith, J. Natl. Cancer Inst. 84, 827-831, 1992; Cobb et al., Crit. Care Med. 21, 1261-1263, 1993; Lorente et al., Crit. Care Med. 21, 1287-1295, 1993). Further, it has been suggested that iNOS inhibitors are useful as therapeutics of chronic rheumatoid arthritis and osteoarthritis (Farrell et al., Ann, Rheum. Dis. 51, 1219-1222, 1992; Hauselmann et al., FEBS Lett. 352, 361-364, 1994; Islante et al., Br. J. Pharmacol. 110, 701-706, 1993), viral or nonviral infections (Zembvitz and Vane, Proc. Natl. Acad. Sci. USA 89, 2051-2055, 1992; Koprowski et al., Proc. Natl. Acad. Sci. USA 90, 3024-3027, 1993) and diabetes mellitus (Kolb et al., Life Sci. PL213-PL217, 1991).

The NOS inhibitors so far reported to have a certain degree of selectivity for nNOS are N^(G)-cyclopropyl-L-arginine (L-CPA)(Lamberte et al., Eur. J. Pharmacol. 216, 131-134, 1992), L-NA (Furfine et al., Biochem. 32, 8512-8517, 1993), S-methyl-L-thiocitrulline (L-MIN) (Narayanan and Griffith, J. Med. Chem. 37, 885-887, 1994; Furfine et al., J. Biol. Chem. 37, 885-887, 1994; Furfine et al. J. Biol. Chem. 269, 26677-26683, 1994; WO95/09619; Narayanan et al., J. Biol. Chem. 270, 11103-11110, 1995; Nagafuji et al., Neuroreport 6, 1541-1545, 1995), S-ethyl-L-thiocitrulline (L-EIN) (Furfine et al., J. Biol. Chem. 269, 26677-26683, 1994; WO95/09619; Narayanan et al., J. Biol. Chem. 270, 11103-11110, 1995), and ARL 17477 (Gentile et al., WO95/05363; Zhang et al., J. Cereb. Blood Flow Metab., 16, 599-604, 1996).

In addition, the inhibitors that have been reported to have a certain degree of selectivity for iNOS are N^(G)-iminoethyl-L-ornithine (L-NIO) (McCall et al., Br. J. Pharmacol. 102, 234-238, 1991) and aminoguanidine (AG) (Griffith et al., Br. J. Pharmacol. 110, 963-968, 1993; Hasan et al. Eur. J. Pharmacol. 249, 101-106, 1993).

DISCLOSURE OF INVENTION

An object of the present invention is to provide novel compounds that have an inhibitory effect on calcium-dependent nNOS which is present constitutively in the brain, particularly in neurons or an inducible and apparently calcium-independent iNOS and which are useful as therapeutics of cerebrovascular diseases [cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction (atherothrombotic infarction, lacunar infarction and cardiogenic embolism), transient ischemic attack and cerebral edema], traumatic brain injury, spinal injury, pains [headache (migraine, tension headache, cluster headache and chronic paroxysmal headache)], Parkinson's disease, Alzheimer's disease, seizure, morphine tolerance or dependence, septic shock, chronic rheumatoid arthritis, osteoarthritis, viral or nonviral infections and diabetes mellitus.

As a result of the intensive studies made in order to attain the stated object, the present inventors found that aromatic amine derivatives represented by the general formula (I), or possible tautomers, stereoisomers and optically active forms of said compounds, as well as pharmaceutically acceptable salts thereof have an inhibitory action on type 1 NOS and so forth, thereby exhibiting marked effectiveness as therapeutics of cerebrovascular diseases (especially as therapeutics of occlusive cerebrovascular diseases):

(where R₁ and R₂ which may be the same or different are each a hydrogen atom, an optionally substituted lower alkyl group, an acyl group or a lower alkoxycarbonyl group, or R₁ and R₂ may combine together to form a 3- to 8-membered ring;

R₃ and R₄ which may be the same or different are each a hydrogen atom, an optionally substituted lower alkyl group, or R₃ and R₄ may combine together to form a monocyclic or fused ring having 3-10 carbon atoms;

R₅ is a hydrogen atom, a lower alkyl group, an acyl group or a lower alkoxycarbonyl group;

X₁, X₂, X₃, and X₄, which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, an optionally substituted lower alkyl group, a lower alkenyl group, a lower alkynyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkylthio group, a phenyl group optionally substituted by a halogen atom and/or a lower alkyl group, NX₅X₆ or C(═O)X₇;

where X₅ and X₆ which may be the same or different are each a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted lower alkoxycarbonyl group, or X₅ and X₆ may combine together to form a 3- to 8-membered ring;

X₇ is a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, or NX₈X₉;

where X₈ and X₉ which may be the same or different are each a hydrogen atom, an optionally substituted lower alkyl group, or x₈ and X₉ may combine together to form a 3- to 8-membered ring;

A is an optionally substituted benzene ring or a 5- or 6-membered aromatic hetero ring which is optionally substituted and which contains at least one nitrogen atom as a hetero atom;

n and m are each an integer of 0 or 1).

The present invention has been accomplished on the basis of this finding.

The present invention also provides a process for producing a compound of the general formula (1) which is represented by the reaction pathway (A):

namely, a process in which a substituted aniline represented by the general formula (2) (where R₁, R₂, R₃, R₄, X₁, X₂, X₃, X₄, n and m have the same meanings as defined above; R₅ is a hydrogen atom or an optionally substituted lower alkyl group) is reacted with a compound represented by the general formula (3) (where A has the same meaning as defined above; L is a leaving group) to produce a compound represented by the general formula (1).

The present invention further provides a process for producing a compound of the general formula (1) which is represented by the reaction pathway (B):

namely, a process in which a substituted benzene represented by the general formula (9) (where R₁, R₂, R₃, R₄, X₁ , X₂, X₃, X₄, L, n and m have the same meanings as defined above) is reacted with a compound represented by the general formula (10) (where A and R₅ have the same meanings as defined above) to produce a compound represented by the general formula (1).

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the 5- or 6-membered aromatic hetero ring as an example of A which contains at least one nitrogen atom as a hetero atom may be exemplified by a pyrrole ring, a pyrrole-1-oxide ring, a pyrazole ring, a pyrazole-1-oxide ring, a pyrazole-2-oxide ring, a pyrazole-1,2-dioxide ring, an imidazole ring, an imidazole-1-oxide ring, an imidazole-3-oxide ring, an imidazole-1,3-dioxide ring, an isoxazole ring, an isoxazole-2-oxide ring, an oxazole ring, an oxazole-3-oxide ring, an isothiazole ring, an isothiazole-1-oxide ring, an isothiazole1,1-dioxide ring, an isothiazole-1,2-dioxide ring, an isothiazole-2-oxide ring, a thiazole ring, a thiazole-1-oxide ring, a thiazole-1,1-dioxide ring, a thiazole-3-oxide ring, a pyridine ring, a pyridine-N-oxide ring, a pyridazine ring, a pyridazine-1-oxide ring, a pyridazine-1,2-dioxide ring, a pyrimidine ring, a pyrimidine-1-oxide ring, a pyrimidine-1,3-dioxide ring, a pyrazine ring, a pyrazine-1-oxide ring or a pyrazine-1,4-dioxide ring or the like;

the substituent in A is a hydroxyl group, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, a lower alkoxy group, a lower alkyl group, a lower alkylthio group, NX₁₀X₁₁ or C(═O)X₁₂;

where X₁₀ and X₁₁ which may be the same or different are each a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted lower alkoxycarbonyl group, or X₁₀ and X₁₁ may combine together to form a 3- to 8-membered ring;

X₁₂ is a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group or NX₁₃X₁₄;

where X₁₃ and X₁₄ which may be the same or different are each a hydrogen atom, an optionally substituted lower alkyl group, or X₁₃ and X₁₄ may combine together to form a 3- to 8-membered ring;

the lower alkyl group is a straight-chained alkyl group having 1-6 carbon atoms, or a branched or cyclic alkyl group having 3-8 carbon atoms and may be exemplified by a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an i-propyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an i-pentyl group, a neopentyl group, a t-pentyl group, an i-hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group or the like;

the lower alkenyl group is a straight-chained alkenyl group having 2-6 carbon atoms or a branched alkenyl group having 3-6 carbon atoms and may be exemplified by a vinyl group, an allyl group, a 1-butenyl group, a 1-pentenyl group, a 1-hexenyl group, a 2-butenyl group, a 2-pentenyl group, a 2-hexenyl group, an isopropenyl group, a 2-butenyl group or a 1-methyl-1-propenyl group or the like;

the lower alkynyl group is a straight-chained alkynyl group having 2-6 carbon atoms or a branched alkynyl group having 3-6 carbon atoms and may be exemplified by an ethynyl group, a 1-propynyl group, a 1-butynyl group, a 1-pentynyl group, a 1-hexynyl group, a 2-propynyl group, a 2-butynyl group, a 2-pentynyl group, a 2-hexynyl group, a 1-methyl-2-propynyl group, a 3-methyl-1-butynyl group or a 1-ethyl-2-propynyl group or the like;

the lower alkoxy group is a straight-chained alkoxy group having 1-6 carbon atoms or a branched or cyclic alkoxy group having 3-8 carbon atoms and may be exemplified by a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, an n-pentoxy group, an n-hexoxy group, an i-propoxy group, an i-butoxy group, a sec-butoxy group, a t-butoxy group, an i-pentoxy group, a neopentoxy group, a t-pentoxy group, an i-hexoxy group, a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a cyclohexoxy group, a cycloheptoxy group or a cyclooctoxy group or the like;

the lower alkylthio group is a straight-chained alkylthio group having 1-6 carbon atoms or a branched or cyclic alkylthio group having 3-8 carbon atoms and may be exemplified by a methylthio group, an ethylthio group, an n-propylthio group, an n-butylthio group, an n-pentylthio group, an n-hexylthio group, an i-propylthio group, an i-butylthio group, a sec-butylthio group, a t-butylthio group, an i-pentylthio group, a neopentylthio group, a t-pentylthio group, an i-hexylthio group, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group or a cyclooctylthio group or the like;

the acyl group is not only a formyl group but also an alkylcarbonyl group the alkyl portion of which is a lower alkyl group, as well as an arylcarbonyl group and may be exemplified by an acetyl group, a propionyl group, a butyryl group, a valeryl group, an isobutyryl group, an isovaleryl group, a pivaloyl group, a benzoyl group, a phthaloyl group or a toluoyl group or the like;

the lower alkoxycarbonyl group is an alkoxycarbonyl group the alkyl portion of which is a lower alkyl group and may be exemplified by a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an n-butoxycarbonyl group, an n-pentoxycarbonyl group, an n-hexoxycarbonyl group, an i-propoxycarbonyl group, an i-butoxycarbonyl group, a sec-butoxycarbonyl group, a t-butoxycarbonyl group, an i-pentoxycarbonyl group, a neopentoxycarbonyl group, a t-pentoxycarbonyl group, an i-hexoxycarbonyl group, a cyclopropoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopentoxycarbonyl group, a cyclohexoxycarbonyl group, a cycloheptoxycarbonyl group, or a cyclooctoxycarbonyl group or the like;

the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom;

the leaving group is a halogen atom, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group or a methanesulfonyloxy group;

the substituent in the case where R₁, R₂, R₃, R₄, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, or X₁₄ is a optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkylthio group or an optionally substituted lower alkoxycarbonyl group may be exemplified by a halogen atom, a phenyl group optionally substituted by a halogen atom or a lower alkyl group or a cyclic alkyl group having 3-8 carbon atoms;

the ring as the 3- to 8-membered ring optionally formed by R₁ and R₂ taken together, the ring as the 3- to 8-membered ring optionally formed by X₅ and X₆ taken together, the ring as the 3- to 8-membered ring optionally formed by X₈ and X₉ taken together, the ring as the 3- to 8-membered ring optionally formed by X₁₀ and X₁₁ taken together, and the ring as the 3- to 8-membered ring optionally formed by X₁₃ and X₁₄ taken together are each a hetero ring containing at least one nitrogen atom as a hetero atom and may be exemplified by a pyrrole ring, a pyrazole ring, an imidazole ring, a triazole ring, an aziridine ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a thiomorpholine ring, an azepane ring or an azocane ring or the like;

the ring as the monocyclic or fused ring having 3-10 carbon atoms that is optionally formed by R₃ and R₄ taken together may be exemplified by a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, an indane ring or a tetralin ring or the like;

NX₅X₆, NX₈X₉, NX₁₀X₁₁, and NX₁₃X₁₄ may be exemplified by an amino group, a methylamino group, a benzylamino group, an ethylamino group, a dimethylamino group, an ethylmethylamino group, a pyrrolidine-1-yl group, a piperidine-1-yl group, a morpholine-4-yl group, an acetamido group, a benzamido group, an N-methylacetamide group, a benzamido group, a tert-butoxycarbonylamino group, an N-methyl-t-butoxycarbonylamino group, a pyrrole-1-yl group, a pyrazole-1-yl group, an imidazole-1-yl group, a triazole-1-yl group, an aziridine-1-yl group, an azetidine-1-yl group, a pyrrolidine-1-yl group, a piperidine-1-yl group, a piperazine-1-yl group, a morpholine-4-yl group or a thiomorpholine-4-yl group or the like;

C(═O)X₇ may be exemplified by a formyl group, a carboxyl group, an acetyl group, a propionyl group, a cyclobutyryl group, a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, a carbamoyl group, an N-methylcarbamoyl group, an N-ethylcarbamoyl group, an N,N-dimethylcarbamoyl group, an N-ethyl-N-methylcarbamoyl group, a pyrrolidinecarbonyl group, a piperidinecarbonyl group or a morpholinecarbonyl group or the like;

R₁ and R₂ are preferably a hydrogen atom;

R₃ and R₄ are preferably a hydrogen atom, a lower alkyl group having 1-3 carbon atoms or a monocyclic ring having 3-5 carbon atoms, with a hydrogen atom, a methyl group, an ethyl group or a cyclobutyl group being particularly preferred;

R₅ is preferably a hydrogen atom;

X₁, X₂, X₃, and X₄ are preferably a hydrogen atom, a halogen atom, a lower alkyl group having 1-3 carbon atoms or a lower alkoxy group having 1-3 carbon atoms, with a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a methoxy group, an ethyoxy group or an n-propoxy group being particularly preferred;

A is preferably an optionally substituted benzene or pyridine ring, and more preferred is a benzene or pyridine ring that is substituted by a nitro group, a lower alkyl group having 1-3 carbon atoms, a lower alkoxy group having 1-3 carbon atoms or a lower alkylthio group having 1-3 carbon atoms, with a 6-methoxy-3-nitrobenzene-2-yl group, a 6-methyl-3-nitropyridine-2-yl group, a 6-methoxy-3-nitropyridine-2-yl group or a 4-methylpyridine-2-yl group being particularly preferred;

m and n are such that if they are both zero, the substituents other than X₁, X₂, X₃, and X₄ are preferably meta-substituted on the benzene nucleus whereas if m+n=1, the substituents other than X₁, X₂, X₃, and X₄ are preferably ortho- or para-substituted on the benzene nucleus.

Preferred compounds represented by the general formula (1) are 2-(3-aminomethylphenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethylphenylamino)-6-methyl-3-nitropyridine, 2-(3-aminomethylphenylamino)-3-ethyl-3-nitropyridine, 2-(3-aminomethylphenylamino)-6-ethoxy-3-nitropyridine, 2-(3-aminomethylphenylamino)-6-methylthio-3-nitropyridine, 2-(3-aminomethylphenylamino)-6-methyl-3-nitrobenzene, 2-(3-aminomethylphenylamino)-6-methoxy-3-nitrobenzene, 2-(3-aminomethyl-2-methylphenylamino)-6-methoxy-3-nitropyridine, 2-(4-aminoethylphenylamino)-6-methoxy-3-nitropyridine, 2-(3-(1-amino-1-methylethyl)phenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethyl-2-methoxyphenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethyl-4-chlorophenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethyl-4-fluorophenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethyl-2-ethoxyphenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethyl-2-chlorophenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethylphenylamino)-4-methylpyridine, 2-(3-(1-amino-1-methylethyl)phenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-methylphenylamino)-4-methylpyridine, 2-(3-aminomethyl-4-ethylphenylamino)-4-methylpyridine, 2-(3-aminomethyl-4-ethoxyphenylamino)-4-methylpyridine, 2-(2-aminoethylphenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-chlorophenylamino)-4-methylpyridine, 2-(3-(1-amino-cyclobutyl)phenylamino)-4-methylpyridine, 2-(4-aminoethylphenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-ethoxyphenylamino)-4-methylpyridine, 2-(3-aminomethyl-4-chlorophenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-(n-propoxy)phenylamino)-4-methylpyridine, 2-(3-aminomethyl-4-chloro-2-ethoxyphenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-ethoxy-4-methylphenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-methoxyphenylamino)-4-methylpyridine and 2-(3-aminomethyl-2-(i-propoxy)phenylamino)-4-methylpyridine.

In addition to the compounds represented by the general formula (1), the present invention also encompasses their possible tautomers, stereoisomers, optionally active forms and mixtures thereof.

The compounds of the invention which are represented by the general formula (1) may typically be synthesized by the following schemes:

The compound represented by the general formula (1) can be synthesized by reacting a compound of the general formula (2), used as a starting material, with a compound of the general formula (3).

In the general formulas (1), (2) and (3), R₁, R₂, R₃, R₄, R₅, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, A, L, n and m each have the same meanings as defined above.

Stated more specifically, the compound represented by the general formula (1) can be synthesized by reacting the compound of the general formula (2) with the compound of the general formula (3) in the presence of a base such as potassium carbonate, triethylamine, diisopropylethylamine, potassium t-butoxide or sodium t-butoxide, with a metal catalyst such as copper, palladium or nickel and a ligand such as diphenylphophinoethane, diphenylphosphinopropane, diphenylphosphinoferrocene or 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl being added as required, in a solvent inert to the reaction as exemplified by an alcohol such as methanol, ethanol or i-propanol or dimethylformamide, tetrahydrofuran, acetonitrile, toluene or 1,4-dioxane, at a temperature between room temperature and the boiling point of the reaction mixture. Preferably synthesis can be made by performing the reaction in the presence of triethylamine or diisopropylethylamine in dimethylformamide at 60° C. or by performing the reaction in the presence of potassium carbonate, potassium t-butoxide or sodium t-butoxide, with a palladium catalyst and a ligand diphenylphosphinoferrocene or 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl added, in acetonitrile or toluene at a temperature between 80° C. and the boiling point of the reaction mixture.

The compound represented by the general formula (1) can also be synthesized by reacting a compound of the general formula (9), used as a starting material, with a compound of the general formula (10).

In the general formulas (1), (9) and (10), R₁, R₂, R₃, R₄, X₁, X₂, X₃, X₄, R₅, A, L, m and n each have the same meanings as defined above.

Stated more specifically, the compound represented by the general formula (1) can be synthesized by reacting the compound of the general formula (9) with the compound of the general formula (10) in the presence of a base such as potassium carbonate, triethylamine, potassium t-butoxide or sodium t-butoxide, preferably in the presence of potassium t-butoxide, with a metal catalyst such as copper, palladium or nickel and a ligand such as diphenylphosphinoethane, diphenylphosphinopropane, diphenylphosphinoferrocene or 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl being added as required, preferably a palladium catalyst and a ligand diphenylphosphinoferrocene being added, in a solvent inert to the reaction as exemplified by an alcohol such as methanol, ethanol or i-propanol or dimethylformamide, tetrahydrofuran, acetonitrile, toluene or dioxane, preferably in toluene, at a temperature between room temperature and the boiling point of the reaction mixture, preferably at 80° C.

Among the compounds represented by the general formula (1), one which is represented by the general formula (5) where A is an optionally substituted pyridine ring and one of the substituents present is a lower alkoxy group, a lower alkylthio group or NX₁₀X₁₁ can also be synthesized starting with a compound of the general formula (4) with the leaving group attached.

In the general formulas (4), (5), (12), (13) and (14),

R₁, R₂, R₃, R₄, X₁, X₂, X₃, X₄, L, m and n each has the same meanings as defined above;

R₆ is an electron withdrawing group such as a nitro group, a cyano group, a trifluoromethyl group or C(═O)X₇;

R₇ and R₈ are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group, a lower alkyl group, a lower alkylthio group, NX,X₆ or C(═O)X₇;

where X₅, X₆, and X₇ each has the same meanings as defined above;

R₁₁ is a lower alkoxy group, a lower alkylthio group or NX₁₀X₁₁;

R₁₂ and X₁ are each a lower alkyl group;

X₁₁ is a hydrogen atom or a lower alkyl group.

Stated more specifically, the compound represented by the general formula (5) can also be synthesized from the compound of the formula (4) by desirably reacting it with a corresponding compound of the general formula (12), (13) or (14) in the presence of a base such as triethylamine or sodium hydride in a solvent inert to the reaction such as dimethylformamide, tetrahydrofuran or acetonitrile at a temperature between room temperature and the boiling point of the reaction mixture.

Among the compounds represented by the general formula (1), one which is represented by the general formula (11) where A is an optionally substituted pyridine ring and one of the substituents present is a lower alkyl group can also be synthesized by decarboxylation a compound obtained by performing a nucleophilic substitution on a lower alkyl dicarbonate corresponding to a compound of the general formula (4) with the leaving group attached.

In the general formulas (4) and (11),

R₁, R₂, R₃, R₄, R₆, R₇, R₈, X₁, X₂, X₃, X₄, m and n each have the same meanings as defined above; and

R₁₄ is a lower alkyl group.

Stated more specifically, the compound represented by the general formula (11) can also be synthesized from the compound of the general formula (4) by desirably reacting it with a corresponding lower alkyl dicarbonate in the presence of a base such as sodium hydride in a solvent inert to the reaction as exemplified by dimethylformamide, tetrahydrofuran or acetonitrile, preferably in dimethylformamide, at a temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature and thereafter subjecting the product to reaction in aqueous sulfuric acid at the boiling point of the reaction mixture.

Examples of the lower alkyl dicarbonate include dimethyl malonate, diethyl malonate, diethyl methylmalonate, diethyl ethylmalonate, diethyl n-propylmalonate, diethyl i-propylmalonate, diethyl n-butylmalonate, diethyl i-butylmalonate, diethyl t-butylmalonate, diethyl n-pentylmalonate and so forth.

Among the compounds represented by the general formula (1), one which is represented by the general formula (7) here A is an optionally substituted pyridine ring and one of the substituents present is an amino group can also be synthesized by reducing the nitro group in the corresponding general formula (6).

In the general formulas (6) and (7),

R₁, R₂, R₃, R₄, m and n each have the same meanings as defined above;

R₆, R₇, and R₈ are each a hydrogen atom, a halogen atom, a trifluoromethyl group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, NX₅X₆ or COX₇;

where X₅, X₆, and X₇ each have the same meanings as defined above;

X₁, X₂, X₃, and X₄ are each a hydrogen atom, a halogen atom, a phenyl group optionally substituted with a halogen atom and/or a lower alkyl group, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, NX₅X₆ or COX₇;

where X₅, X₆, and X₇, each have the same meanings as defined above.

Stated more specifically, the compound represented by the general formula (7) can also be synthesized by subjecting the compound of the general formula (6) to catalytic reduction in a solvent inert to the reaction as exemplified by ethanol, methanol, ethyl acetate, acetic acid or 1,4-dioxane, preferably in ethanol or methanol, in a hydrogen atmosphere at a temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature, with palladium-carbon, Raney nickel or platinum oxide used as a catalyst, or by performing reduction using nickel (II) chloride or sodium borohydride, so as to reduce the nitro group.

Among the compounds represented by the general formula (1), one which is represented by the general formula (8) where A is an optionally substituted pyridine ring and one of the substituents present is NR₉R₁₀, can also be synthesized with a compound of the general formula (7) used as a starting material.

In the general formulas (7), (8), (15), (16) and (17),

R₁, R₂, R₃ , R₄, R₆, R₇, R₈, R₁₂, X₁, X₂, X₃, X₄, L, m and n each have the same meanings as defined above;

R₉ is a hydrogen atom or a lower alkyl group;

R₁₀ is a lower alkyl group, an acyl group or a lower alkoxycarbonyl group;

R₁₃ is a lower alkyl group optionally substituted by a phenyl group; and

X is a halogen atom.

Stated more specifically, the compound represented by the general formula (8) can also be synthesized from the compound of the general formula (7) by desirably reacting it with a corresponding compound of the general formula (15), (16) or (17) in the presence of a base such as triethylamine or potassium carbonate in a solvent inert to the reaction at a temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature.

If in the process of synthesizing the compounds represented by the above formulas (1), (5), (7), (8) and (11), a protective group is necessary for the primary or secondary amino group, they are first protected either with a suitable resin or with one of the appropriate protective groups described in Green and Wuts, “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS”, 2nd Edition, John Wiley & Sons Inc., p. 309, 1991, and thereafter the respective reactions are performed. If necessary, the protected groups may be subjected to a deprotecting reaction. Examples of the amino protecting group include a t-butoxycarbonyl group, a trifluoroacetyl group and so forth.

The amino protecting reaction such as t-butoxycarbonylation may be performed by reacting the respective compound with di-t-butyl dicarbonate in a solvent inert to the reaction as exemplified by an alcohol such as methanol, ethanol or i-propanol or methylene dichloride, dimethyl-formamide or 1,4-dioxane in the presence of an organic base such as triethylamine or 4-dimethylamiopyridine at a temperature between 0° C. and room temperature.

The amino protecting reaction may also be performed with a Wang resin by reacting the respective compound with a 4-nitrophenyloxycarbonyl-Wang resin (Tetrahedron Lett., 37, 937-940 (1996)) in a solvent inert to the reaction as exemplified by methylene chloride, dimethylformamide or 1,4-dioxane in the presence of an organic base such as 4-methylmorpholine, triethylamine or 4-dimethylaminopyridine at a temperature between 0° C. and room temperature.

If the protecting group is a t-butoxycarbonyl group or the Wang resin mentioned above, a reaction for deprotecting the amino group is preferably performed in a solvent inert to the reaction as exemplified by methanol, ethanol, 1,4-dioxane or methylene chloride or without using any solvent at all, with the aid of a deprotecting agent such as trifluoroacetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid at a temperature between 0° C. and room temperature, with the use of anhydrous conditions, room temperature and trifluoroacetic acid being particularly preferred.

If the compounds of the invention which are represented by the general formula (1) have asymmetric carbons in their structure, the pure forms of their stereoisomers and optically active forms can be obtained by known techniques in the art, such as chromatography on optical isomer separating columns and fractional crystallization.

Pharmaceutically acceptable salts of the compounds of the invention which are represented by the general formula (1) may be of any types as long as they are pharmaceutically acceptable salts and typical examples include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobrobromic acid and hydroiodic acid, salts with organic acids such as formic acid, acetic acid, oxalic acid and tartaric acid, salts with alkali metals such as sodium and potassium, and salts with alkaline earth metals such as calcium and magnesium.

The compounds of the invention or salts thereof may be formulated with suitable excipients, adjuvants, lubricants, antiseptics, disintegrators, buffering agents, binders, stabilizers, wetting agents, emulsifiers, coloring agents, flavoring agents, fragrances, etc. to form tablets, granules, subtilized granules, powders, capsules, syrups, elixirs, suspensions, emulsions, injections, etc. for oral or parenteral administration. When the cerebrovascular diseases to be treated are in a hyperacute phase (immediately after the stroke), an acute phase (from the stroke to 2 or 3 days later) or in a subacute phase (2 or 3 days up to 2 weeks after the stroke), administration is effected primarily by intramuscular or intravenous injection. In addition, oral administration may be performed in a chronic phase (the third week after stroke and onward) if the patient admits ingestion.

The compounds of the invention or salts thereof may be administered in doses that vary with the physical constitution of the patient, his or her age, physical condition, the severity of the disease, the time of lapse after the onset of the disease and other factors; typical daily doses range from 0.5 to 5 mg/body for oral administration and from 1 to 10 mg/body for parenteral administration. It should generally be noted that even if the same dose is administered, the plasma concentration may sometimes vary considerably between patients; hence, an optimal dose of the drug should ideally be determined for each patient on the basis of a monitored plasma concentration of the drug.

If the compounds of the invention or salts thereof are to be formulated as preparations for internal application, lactose, sucrose, sorbitol, mannitol, starches such as potato starch or corn starch, starch derivatives and common additives such as cellulose derivatives or gelatin are suitably used as vehicles, with lubricants such as magnesium stearate, carbowaxes and polyethylene glycol being optionally added concurrently; the resulting mixtures may be formulated in the usual manner into granules, tablets, capsules or other forms suitable for internal application.

If the compounds of the invention or salts thereof are to be formulated as aqueous preparations, effective amounts of the principal ingredients may be dissolved in distilled water for injection, with antioxidants, stabilizers, dissolution aids, buffering agents, preservatives, etc. added as required and, after complete solutions are formed, they are filtered, filled into ampules and sealed in the usual manner and sterilized by a suitable medium such as high-pressure vapor or dry heat so as to prepare injections.

If the compounds of the invention or salts thereof are to be formulated as lyophilized preparations, aqueous solutions having the principal ingredients dissolved in distilled water for injection may be freeze-dried in the usual manner; depending on the need, excipients that provide for easy lyophilization, such as sugars (e.g. lactose, maltose and sucrose), sugar alcohols (e.g. mannitol and inositol), glycine and the like, may be added before freeze-drying is performed in the usual manner to make the intended preparations.

EXAMPLES

Lists of the compounds prepared in the Examples of the invention are given in Tables 1-37 below.

TABLE 1

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 1 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 2 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 3 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 4 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 5 (2) CR₆ N NHMe 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 6 (2) CR₆ N NHMe 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 7 (2) CR₆ N NHEt 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 8 (2) CR₆ N NHEt 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 9 (2) CR₆ N H 2 4-H 5-NO₂ 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 10 (2) CR₆ N H 2 4-H 5-NO₂ 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 11 (2) CR₆ N H 2 4-H 5-NH₂ 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 12 (2) CR₆ N H 2 4-H 5-NH₂ 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 13 (2) CR₆ N NO₂ 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 14 (2) CR₆ N NO₂ 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 15 (2) CR₆ N NO₂ 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 2

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 16 (2) CR₆ N NH₂ 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 17 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 18 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 19 (2) CR₆ N NH₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 20 (2) CR₆ N NH₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 21 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-OMe 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 22 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-OMe 5-H 6-H 3 H H 0 H H 0 H HCl 23 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-Et 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 24 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-Et 5-H 6-H 3 H H 0 H H 0 H HCl 25 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-Et 5-H 6-H 3 CO₂ ^(t)Bu H 0 indan-2-yl 0 H 26 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-Et 5-H 6-H 3 H H 0 indan-2-yl 0 H HCl 27 (2) CR₆ N NO₂ 2 4-H 5-H 6-Cl 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 28 (2) CR₆ N NO₂ 2 4-H 5-H 6-Cl 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 29 (2) CR₆ N NO₂ 2 4-H 5-H 6-NHMe 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 30 (2) CR₆ N NO₂ 2 4-H 5-H 6-NHMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 3

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 31 (2) CR₆ N NO₂ 2 4-H 5-H 6-NHEt 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 32 (2) CR₆ N NO₂ 2 4-H 5-H 6-NHEt 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 33 (2) CR₆ N NO₂ 2 4-H 5-H 6-NH^(n)Pr 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 34 (2) CR₆ N NO₂ 2 4-H 5-H 6-NH^(n)Pr 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 35 (2) CR₆ N NO₂ 2 4-H 5-H 6-NMe₂ 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 36 (2) CR₆ N NO₂ 2 4-H 5-H 6-NMe₂ 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 37 (2) CR₆ N CO₂H 2 4-H 5-H 6-Cl 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 38 (2) CR₆ N CO₂H 2 4-H 5-H 6-Cl 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 39 (2) CR₆ N H 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 40 (2) CR₆ N H 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 41 (2) CR₆ N CF₃ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 42 (2) CR₆ N CF₃ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 43 (2) CR₆ N CO₂Me 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 44 (2) CR₆ N CO₂Me 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 45 (2) CR₆ N CO₂H 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 4

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 46 (2) CR₆ N H 2 4-OBn 5-H 6-H 2-H 4-H 5-H 6-H 3 Ac H 0 H H 0 H HCl 47 (2) CR₆ N H 2 4-OBn 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 48 (2) CR₆ N H 2 4-H 5-H 6-H 2-H 4-cyclobutyl 5-H 6-H 3 Bz H 0 H H 0 H HCl 49 (2) CR₆ N H 2 4-H 5-H 6-H 2-H 4-cyclopentyl 5-H 6-H 3 H H 0 H H 0 H HCl 50 (2) CR₆ N H 2 4-H 5-H 6-H 2-H 4-piperidino 5-H 6-H 3 H H 0 H H 0 H 2HCl 51 (2) CR₆ N H 2 4-H 5-H 6-H 2-H 4-O(CH₂)₂Ph 5-H 6-H 3 H H 0 H H 0 H 2HCl 52 (2) CR₆ N NO₂ 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 53 (2) CR₆ N NO₂ 2 4-H 5-H 6-Et 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 54 (2) CR₆ N NO₂ 2 4-H 5-H 6-^(n)Pr 2-H 4-H 5-H 6-H 3 Bn H 0 H H 0 H HCl 55 (2) CR₆ N NO₂ 2 4-H 5-H 6-^(i)Pr 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 56 (2) CR₆ N NO₂ 2 4-H 5-H 6-OH 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 57 (2) CR₆ N NO₂ 2 4-H 5-H 6-OEt 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 58 (2) CR₆ N NO₂ 2 4-H 5-H 6-O^(n)Pr 2-H 4-H 5-H 6-H 3 CH₂CH₂Ph H 0 H H 0 H HCl 59 (2) CR₆ N NO₂ 2 4-H 5-H 6-O^(i)Pr 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 60 (2) CR₆ N NO₂ 2 4-H 5-H 6-SH 2-H 4-H 5-H 6-H 3 CH₂CH₂Cl CH₂CH₂Cl 0 H H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 5

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 61 (2) CR₆ N NO₂ 2 4-H 5-H 6-SMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 62 (2) CR₆ N NO₂ 2 4-H 5-H 6-SEt 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 63 (2) CR₆ N NO₂ 2 4-H 5-H 6-S^(n)Pr 2-H 4-H 5-H 6-H 3 H H 0 H H 0 Me HCl 64 (2) CR₆ N NO₂ 2 4-H 5-H 6-S^(i)Pr 2-H 4-H 5-H 6-H 3 H H 0 H H 0 Et HCl 65 (2) CR₆ N H 2 4-NO₂ 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 66 (2) CR₆ N H 2 4-NO₂ 5-H 6-Et 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 67 (2) CR₆ N H 2 4-H 5-NO₂ 6-OMe 2-H 4-H 5-NHAc 6-H 3 H H 0 H H 0 H HCl 68 (2) CR₆ N H 2 4-H 5-NO₂ 6-Et 2-H 4-NHBn 5-H 6-H 3 H H 0 H H 0 H HCl 69 (2) CR₆ N CO₂H 2 4-H 5-H 6-OMe 2-H 4-NO₂ 5-H 6-H 3 H H 0 H H 0 ^(n)Pr HCl 70 (2) CR₆ N CO₂H 2 4-H 5-H 6-Et 2-H 4-H 5-NO₂ 6-H 3 H H 0 H H 0 Ac HCl 71 (2) CR₆ N CO₂Me 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 Bn HCl 72 (2) CR₆ N CO₂Me 2 4-H 5-H 6-Et 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 73 (2) CR₆ N CONH₂ 2 4-H 5-H 6-OMe 2-H 4-F 5-H 6-H 3 H H 0 H H 0 H 2HCl 74 (2) CR₆ N CONH₂ 2 4-H 5-H 6-Et 2-H 4-H 5-Br 6-H 3 H H 0 H H 0 H 2HCl 75 (2) CR₆ N CF₃ 2 4-H 5-H 6-OMe 2-H 4-CH₂Br 5-H 6-H 3 H H 0 H H 0 H 2HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 6

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 76 (2) CR₆ N CF₃ 2 4-H 5-H 6-Et 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 77 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-Me 5-H 6-H 3 H H 0 H H 0 H HCl 78 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-^(n)Pr 5-H 6-H 3 H H 0 H H 0 H HCl 79 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-NHMe 5-H 6-H 3 H H 0 H H 0 H 2HCl 80 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-NHEt 5-H 6-H 3 H H 0 H H 0 H 2HCl 81 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-NMe₂ 5-H 6-H 3 H H 0 H H 0 H 2HCl 82 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-pyrrolidin-1-yl 5-H 6-H 3 H H 0 H H 0 H 2HCl 83 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-OH 5-H 6-H 3 H H 0 H H 0 H HCl 84 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-OEt 5-H 6-H 3 H H 0 H H 0 H HCl 85 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-H 5-Me 6-H 3 H H 0 H H 0 H HCl 86 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-F 4-H 5-Et 6-H 3 H H 0 CH₂CH₂OH CH₂CH₂OH 0 H HCl 87 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-Cl 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 88 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-Me 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 89 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-OH 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 90 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-OMe 4-H 5-H 6-H 3 H H 0 H H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 7

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 91 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 Me H 0 H HCl 92 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-CN 5-H 6-H 3 H H 0 Et H 0 H HCl 93 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-CN 5-H 6-H 3 H H 0 ^(n)Pr H 0 H HCl 94 (2) CR₆ N NO₂ 2 4-H 5-H 6-cyclobutylthio 2-H 4-H 5-H 6-H 3 H H 0 Me Me 0 H HCl 95 (2) CR₆ N NO₂ 2 4-H 5-H 6-cyclopentylthio 2-H 4-H 5-H 6-H 3 H H 0 —(CH₂)₂— 0 H HCl 96 (2) CR₆ N NO₂ 2 4-H 5-H 6-cyclohexylthio 2-H 4-H 5-H 6-H 3 H H 0 —(CH₂)₃— 0 H HCl 97 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 —(CH₂)₄— 0 H HCl 98 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 Me H 0 H H 0 H HCl 99 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 Et H 0 H H 0 H HCl 100 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-OMe 4-H 5-H 6-H 3 Me Me 0 H H 0 H HCl 101 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-OMe 4-H 5-H 6-H 3 —(CH₂)₃— 0 H H 0 H HCl 102 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 —(CH₂)₄— 0 H H 0 H HCl 103 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 —(CH₂)₅— 0 H H 0 H HCl 104 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 CH₂OH H 0 H HCl 105 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 CH₂CH₂OH H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 8

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 106 (2) CR₆ N H 2 4-OMe 5-H 6-NO₂ 2-H 4-Ph 5-H 6-H 3 H H 0 H H 0 H HCl 107 (2) CR₆ N OH 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 108 (2) CR₆ N CHO 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 109 (2) CR₆ N CO₂H 4 2-H 5-H 6-Et 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 110 (2) CR₆ N CONH₂ 4 2-H 5-H 6-Et 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 111 (2) CR₆ N CO₂Me 4 2-H 5-H 6-OMe 2-H 4-H 5-Me 6-Me 3 H H 0 H H 0 H HCl 112 (2) CR₆ N CN 4 2-H 5-H 6-Et 2-Me 4-Me 5-H 6-H 3 H H 0 H H 0 H HCl 113 (2) CR₆ N CF₃ 5 2-Me 4-H 6-H 2-H 4-H 5-Br 6-H 3 H H 0 H H 0 H 2HCl 114 (2) CR₆ N NO₂ 4 2-H 5-OEt 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 115 (2) CR₆ N H 5 2-H 4-NO₂ 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 116 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 Me HCl 117 (2) CR₆ N NO₂ 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 H H 0 Et HCl 118 (2) CR₆ N NO₂ 2 4-H 5-H 6-Et 2-H 4-H 5-H 6-H 3 H H 0 H H 0 ^(n)Pr HCl 119 (2) CR₆ N NO₂ 2 4-H 5-H 6-OEt 2-H 4-H 5-H 6-H 3 H H 0 H H 0 Ac HCl 120 (2) CR₆ N NO₂ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 Bz HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 9

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 121 (2) CR₆ N NO₂ 2 4-H 5-H 6-SMe 2-H 4-H 5-H 6-H 2 H H 0 H H 0 CO₂Me HCl 122 (2) CR₆ N NO₂ 2 4-H 5-H 6-SEt 2-H 4-H 5-H 6-H 2 H H 0 H H 0 CO₂Et HCl 123 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-Ph 6-H 2 H H 0 Me Me 0 H HCl 124 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-CONH₂ 5-H 6-H 2 H H 0 CH₂OH H 0 H HCl 125 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-Me 4-H 5-H 6-H 2 H H 0 CH₂Br H 0 H HCl 126 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-Me 4-H 5-H 6-H 2 H H 0 H H 0 H HCl 127 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-CH₂OH 4-H 5-H 6-H 2 H H 0 H H 0 H HCl 128 (2) CR₆ N CO₂H 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 2 H H 0 Bn H 0 H HCl 129 (2) CR₆ N CO₂H 2 4-H 5-H 6-Me 2-Me 4-H 5-H 6-H 2 H H 0 CH₂CH₂Ph H 0 H HCl 130 (2) CR₆ N CO₂H 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-H 2 H H 0 CH₂OH H O H HCl 131 (2) CR₆ N CO₂Me 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-NO₂ 2 H H 0 H H 0 H HCl 132 (2) CR₆ N CO₂Me 2 4-H 5-H 6-Me 2-Cl 4-OMe 5-H 6-H 2 H H 0 H H 0 H HCl 133 (2) CR₆ N CO₂Me 2 4-H 5-H 6-OMe 2-H 4-NHAC 5-H 6-H 2 H H 0 H H 0 H HCl 134 (2) CR₆ N CO₂Me 2 4-H 5-H 6-Et 2-Me 4-H 5-H 6-H 2 H H 0 H H 0 H HCl 135 (2) CR₆ N CO₂Me 2 4-H 5-H 6-Et 2-H 4-CONH₂ 5-H 6-H 2 CH₂CH₂F H 0 H H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 10

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 136 (2) CR₆ N H 4 2-CONMe₂ 5-H 6-OMe 3-H 4-H 5-H 6-H 2 H H 1 H H 0 H 2HCl 137 (2) CR₆ N H 4 2-CONHMe 5-H 6-Et 3-H 4-H 5-H 6-H 2 H H 1 H H 0 H 2HCl 138 (2) CR₆ N H 4 2-NHAC 5-H 6-H 3-H 4-H 5-H 6-H 2 H H 1 H H 0 H 2HCl 139 (2) CR₆ N H 4 2-NHCO₂Me 5-H 6-H 3-H 4-H 5-H 6-H 2 H H 1 H H 0 H 2HCl 140 (2) CR₆ N H 4 2-NHBz 5-H 6-H 2-H 4-H 5-H 6-H 2 H H 1 H H 0 H 2HCl 141 (2) CR₆ N NO₂ 5 2-H 4-H 6-F 2-H 4-H 5-H 6-H 2 H H 1 H H 0 H HCl 142 (2) CR₆ N NO₂ 5 2-H 4-H 6-Br 2-H 3-H 5-H 6-H 4 H H 0 H H 1 H HCl 143 (2) CR₆ N NO₂ 5 2-H 4-H 6-H 2-CO₂H 3-H 5-H 6-H 4 H H 0 H H 1 H HCl 144 (2) CR₆ N NO₂ 5 2-H 4-H 6-H 2-H 3-CO₂Me 5-H 6-H 4 H H 0 H H 1 H HCl 145 (2) CR₆ N NO₂ 5 2-H 4-H 6-H 2-H 3-CONHMe 5-H 6-H 4 H H 0 H H 1 H HCl 146 (2) CR₆ N NO₂ 5 2-H 4-H 6-H 2-H 3-H 5-CHO 6-H 4 H H 0 H H 1 H HCl 147 (2) CR₆ N H 2 3-H 4-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 CHO HCl 148 (2) CR₆ N → O H 2 3-H 4-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 149 (2) CR₆ N → O H 2 3-H 4-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 150 (2) CR₆ N → O H 2 3-H 4-H 6-Et 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 11

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 151 (2) CR₆ CH NO₂ 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 152 (2) CR₆ CH NO₂ 2 4-H 5-H 6-Et 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 153 (2) CR₆ CH NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 154 (2) CR₆ CH NO₂ 2 4-H 5-NHMe 6-H 2-H 4-H 5-H 6-H 3 CH₂CH₂F CH₂CH₂F 0 H H 0 H 2HCl 155 (2) CR₆ CH NO₂ 2 4-H 5-NMe₂ 6-H 2-H 4-H 5-H 6-H 3 CH₂CH₂Cl CH₂CH₂Cl 0 H H 0 H 2HCl 156 (2) CR₆ CH NO₂ 2 4-H 5-NHEt 6-H 2-H 4-H 5-H 6-H 3 CH₂CH₂Br CH₂CH₂Br 0 H H 0 H 2HCl 157 (2) CR₆ CH NO₂ 2 4-SMe 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 158 (2) CR₆ CH NO₂ 2 4-SEt 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 159 (2) CR₆ CH NO₂ 2 4-S^(n)Pr 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 160 (2) CR₆ CH CO₂H 2 4-H 5-H 6-Me 2-Me 4-H 5-H 6-H 3 H H 0 —(CH₂)₂— 0 H HCl 161 (2) CR₆ CH CO₂H 2 4-H 5-H 6-^(n)Pr 2-H 4-Et 5-H 6-H 3 H H 0 —(CH₂)₃— 0 H HCl 162 (2) CR₆ CH CO₂H 2 4-H 5-H 6-NH^(n)Pr 2-H 4-H 5-^(n)Pr 6-H 3 H H 0 —(CH₂)₄— 0 H 2HCl 163 (2) CR₆ CH CO₂H 2 4-H 5-H 6-F 2-NHBn 4-H 5-H 6-H 3 —(CH₂)₂— 0 H H 0 H 2HCl 164 (2) CR₆ CH CO₂H 2 4-H 5-H 6-Cl 2-H 4-NHEt 5-H 6-H 3 —(CH₂)₃— 0 H H 0 H 2HCl 165 (2) CR₆ CH CO₂H 2 4-H 5-H 6-Br 2-H 4-H 5-H 6-SEt 3 —(CH₂)₄— 0 H H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 12

Substitution Substitution Ex. position of position of No. A Y Z R₆ A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² W* R₁ R₂ n R₃ R₄ m R₅ salt 166 (2) CR₆ CH CO₂Me 2 4-H 5-H 6-Me 2-H 4-pyrrolidin-1-yl 5-H 6-H 3 H H 0 H H 0 H 2HCl 167 (2) CR₆ CH CO₂Me 2 4-H 5-H 6-Et 2-H 4-pyrrolidin-1-yl 5-H 6-H 3 H H 0 H H 0 H 2HCl 168 (2) CR₆ CH CO₂Me 2 4-H 5-H 6-OMe 2-OMe 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 169 (2) CR₆ CH H 2 4-H 5-CONH₂ 6-Me 2-OEt 4-H 5-H 6-H 3 Bn H 0 H H 0 H HCl 170 (2) CR₆ CH H 2 4-H 5-CONH₂ 6-Me 2-H 4-OBn 5-H 6-H 3 CH₂CH₂Ph H 0 H H 0 H HCl 171 (2) CR₆ CH H 2 4-H 5-CONMe₂ 6-Me 2-F 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 172 (2) CR₆ CH H 2 4-H 5-CONMe₂ 6-Me 2-Cl 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 173 (2) CR₆ CH H 2 4-NHAc 5-H 6-Me 2-Br 4-H 5-H 6-H 3 Ac H 0 H H 0 H 174 (2) CR₆ CH H 2 4-NHAc 5-H 6-Et 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 175 (2) CR₆ CH H 2 4-NHAc 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 176 (2) CR₆ CH H 2 4-NHBn 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 Me H 0 H HCl 177 (2) CR₆ CH H 2 4-NHBn 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 Me Me 0 H HCl 178 (2) CR₆ CH H 2 4-NHBz 5-H 6-Me 2-H 4-H 5-H 6-H 3 Bz H 0 Me Et 0 H 179 (2) CR₆ CH CF₃ 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 Bn H 0 H HCl 180 (2) CR₆ CH CF₃ 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 CH₂OH H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 13

Sunstitution Substitution Ex. position of position of No. A Y Z R₆ A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² W* R₁ R₂ n R₃ R₄ m R₅ salt 181 (2) CR₆ CH CN 2 4-H 5-H 6-cyclobutyl 2-H 4-OH 5-H 6-H 3 H H 0 H H 0 H HCl 182 (2) CR₆ CH CN 2 4-H 5-H 6-cyclopentyl 2-H 4-H 5-CN 6-H 3 H H 0 H H 0 H HCl 183 (2) CR₆ CH CN 2 4-H 5-H 6-cyclohexyl 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 184 (2) CR₆ CH OH 2 4-H 5-H 6-H 2-H 4-H 5-H 6-NO₂ 3 H H 0 CH₂CH₂OH CH₂CH₂OH 0 H 2HCl 185 (2) CR₆ CH OH 2 4-H 5-H 6-H 2-H 4-H 5-H 6-OH 3 H H 0 H H 0 H 2HCl 186 (2) CR₆ CH NH₂ 2 4-H 5-NHCOMe 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 187 (2) CR₆ CH NH₂ 2 4-H 5-NHCO₂Me 6-H 2-H 4-CH₂Ph 5-H 6-H 3 H H 0 H H 0 H 2HCl 188 (2) CR₆ CH NH₂ 2 4-H 5-CHO 6-H 2-H 4-CH₂OH 5-H 6-H 3 H H 0 H H 0 H 2HCl 189 (2) CR₆ CH NH₂ 2 4-H 5-H 6-H 2-CH₂OH 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 190 (2) CR₆ CMe CHO 2 4-H 5-H 6-cyclobutylthio 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 191 (2) CR₆ CH CHO 2 4-H 5-H 6-cyclopentylthio 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 192 (2) CR₆ CH CHO 2 4-H 5-H 6-cyclohexylthio 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 193 (2) CR₆ CH NO₂ 2 4-H 5-H 6-H 2-OH 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 194 (2) CR₆ CH NO₂ 2 4-H 5-H 6-H 2-CN 4-H 5-H 6-H 3 Me H 0 H H 0 H HCl 195 (2) CR₆ CH NO₂ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-NO₂ 3 Me Me 0 H H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 14

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 196 (2) CR₆ CH H 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-NO₂ 3 H Me 0 Me H 0 H HCl 197 (2) CR₆ CH H 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-NO₂ 3 Me Me 0 H H 0 H HCl 198 (2) CR₆ CEt H 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-NO₂ 3 H H 0 H H 0 H HCl 199 (2) CR₆ CH H 2 4-H 5-H 6-Et 2-H 4-H 5-H 6-NO₂ 3 H H 0 H H 0 H HCl 200 (2) CR₆ CH H 2 4-H 5-H 6-Et 2-H 4-H 5-H 6-NO₂ 3 H H 0 H H 0 Ac HCl 201 (2) CR₆ CH H 2 4-H 5-H 6-Et 2-H 4-H 5-H 6-NO₂ 3 H H 0 H H 0 Me HCl 202 (2) CR₆ CH H 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-NO₂ 3 H H 0 H H 0 Ac HCl 203 (2) CR₆ CH H 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-NO₂ 3 H H 0 H H 0 ^(n)Pr HCl 204 (2) CR₆ CH NO₂ 2 4-H 5-H 6-Me 2-H 3-H 5-H 6-H 4 H H 0 H H 1 CO₂Me HCl 205 (2) CR₆ C^(n)Pr NO₂ 2 4-H 5-H 6-Me 2-H 3-H 5-H 6-H 4 H H 0 H H 1 CO₂Et HCl 206 (2) CR₆ CH NO₂ 2 4-H 5-H 6-Me 2-H 3-H 5-H 6-H 4 H H 0 CH₂OH H 1 H HCl 207 (2) CR₆ CH NO₂ 2 4-H 5-H 6-Me 2-H 3-H 5-H 6-H 4 H H 0 CH₂Ph H 1 H HCl 208 (2) CR₆ CH NO₂ 2 4-H 5-H 6-OMe 2-H 3-H 4-H 6-H 5 H H 1 H H 0 H HCl 209 (2) CR₆ CH NO₂ 2 4-H 5-H 6-OMe 2-H 3-H 4-H 6-H 5 H H 1 CH₂CH₂Ph H 0 H HCl 210 (2) CR₆ CH NO₂ 2 4-H 5-H 6-OMe 2-H 3-H 4-H 6-H 5 H H 1 CH₂Ph H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 15

Substitution Substitution Ex. No. A Y Z position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 211 (2) N N 2 4-NO₂ 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 212 (2) N N 2 4-NO₂ 5-H 6-Et 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 213 (2) N N 2 4-NO₂ 5-H 6-^(n)Pr 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 214 (2) N N 2 4-NO₂ 5-H 6-^(i)Pr 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 215 (2) N N 2 4-CO₂H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 216 (2) N N 2 4-CO₂H 5-H 6-OEt 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 217 (2) N N 2 4-CO₂H 5-H 6-O^(n)Pr 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 218 (2) N N 2 4-CO₂H 5-H 6-O^(i)Pr 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 219 (2) N N 2 4-CO₂Me 5-H 6-NHMe 2-H 4-H 5-H 6-H 3 Bn H 0 H H 0 H HCl 220 (2) N N 2 4-CO₂Me 5-H 6-NMe₂ 2-H 4-H 5-H 6-H 3 CH₂CH₂Ph H 0 H H 0 H HCl 221 (2) N N 2 4-CO₂Et 5-H 6-NHEt 2-H 4-H 5-H 6-H 3 CH₂(CH₂)₂Ph H 0 H H 0 H HCl 222 (2) N N 2 4-CO₂Et 5-H 6-NH^(n)Pr 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 223 (2) N N 2 4-CO₂Et 5-H 6-H 2-Me 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 224 (2) N N 2 4-CO₂ ^(n)Pr 5-H 6-H 2-Et 4-H 5-H 6-H 3 H H 0 Bn H 0 H HCl 225 (2) N N 2 4-CO₂ ^(n)Pr 5-H 6-H 2-^(n)Pr 4-H 5-H 6-H 3 H H 0 CH₂CH₂Ph H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 16

Substitution Ex. No. A Y Z position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 226 (2) N N 4 2-CF₃ 5-H 6-H 2-H 4-OMe 5-H 6-H 227 (2) N N 4 2-CF₃ 5-H 6-H 2-H 4-OEt 5-H 6-H 228 (2) N N 4 2-CF₃ 5-H 6-H 2-H 4-O^(n)Pr 5-H 6-H 229 (2) N N 4 2-H 5-CN 6-H 2-H 3-H 5-NHMe 6-H 230 (2) N N 4 2-H 5-CN 6-H 2-H 3-H 5-NHEt 6-H 231 (2) N N 4 2-H 5-CN 6-H 2-H 3-H 5-NH^(n)Pr 6-H 232 (2) N N 4 2-H 5-H 6-CONH₂ 2-H 3-H 5-H 6-SMe 233 (2) N N 4 2-H 5-H 6-CONH₂ 2-H 3-H 5-H 6-SEt 234 (2) N N 4 2-H 5-H 6-CONH₂ 2-H 3-H 5-H 6-S^(n)Pr 235 (2) N N 5 2-OMe 4-H 6-H 3-H 4-H 5-H 6-NO₂ 236 (2) N N 5 2-OEt 4-H 6-H 3-H 4-H 5-H 6-NO₂ 237 (2) N N 5 2-H 4-cyclopropyl 6-H 3-H 4-H 5-H 6-NO₂ 238 (2) N N 5 2-H 4-cyclobutyl 6-H 3-H 4-H 5-H 6-NO₂ 239 (2) N N 5 2-H 4-cyclopentyl 6-H 3-H 4-H 5-H 6-CO₂H 240 (2) N N 5 2-H 4-cyclohexyl 6-H 3-H 4-H 5-H 6-CO₂H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 226 3 H H 0 H H 0 H 2HCl 227 3 H H 0 H H 0 H 2HCl 228 3 H H 0 H H 0 H 2HCl 229 4 Ac H 1 H H 0 H HCl 230 4 Bz H 1 H H 0 H HCl 231 4 CO₂ ^(t)Bu H 1 H H 0 H 232 4 H H 1 H H 0 H 2HCl 233 4 H H 1 H H 0 H 2HCl 234 4 H H 1 H H 0 H 2HCl 235 2 Me H 1 H H 0 H 2HCl 236 2 Me Me 1 H H 0 H 2HCl 237 2 Et H 1 H H 0 H 2HCl 238 2 Et Et 1 H H 0 H 2HCl 239 2 CH₂CH₂Cl CH₂CH₂Cl 1 H H 0 H 2HCl 240 2 CH₂CH₂Br CH₂CH₂Br 1 H H 0 H 2HCl ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 17

Substitution Ex. No. A Y Z position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 241 (2) N N 2 4-CHO 5-H 6-H 2-H 4-NHAc 5-H 6-H 242 (2) N N 2 4-CHO 5-H 6-H 2-H 4-NHBz 5-H 6-H 243 (2) N N 2 4-NH₂ 5-H 6-H 2-H 4-H 5-CONH₂ 6-H 244 (2) N N 2 4-NH₂ 5-H 6-H 2-H 4-H 5-CONHMe 6-H 245 (2) N N 2 4-NH₂ 5-H 6-H 2-H 4-H 5-CONHEt 6-H 246 (2) N N 2 4-H 5-OH 6-H 2-H 4-H 5-H 6-CO₂Me 247 (2) N N 2 4-H 5-OH 6-H 2-H 4-H 5-H 6-CO₂Et 248 (2) N N 2 4-H 5-H 6-pyrrolidin-1-yl 2-H 4-H 5-H 6-CO₂ ^(n)Pr 249 (2) N N 2 4-H 5-H 6-piperidino 2-H 4-CH₂OH 5-H 6-H 250 (2) N N 2 4-H 5-H 6-H 2-H 4-F 5-H 6-H 251 (2) N N 2 4-H 5-H 6-H 2-H 4-Cl 5-H 6-H 252 (2) N N 2 4-H 5-H 6-H 2-H 4-Br 5-H 6-H 253 (2) N→O N→O 2 4-H 5-H 6-H 2-H 4-H 5-CH₂Br 6-H 254 (2) N→O N→O 2 4-H 5-H 6-H 2-H 4-H 5-CN 6-H 255 (2) N→O N→O 2 4-H 5-H 6-H 2-H 4-H 5-CF₃ 6-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 241 3 —CH₂CH₂— 0 H H 0 H HCl 242 3 —CH₂CH₂CH₂— 0 H H 0 H HCl 243 3 —CH₂(CH₂)₂CH₂— 0 H H 0 H 2HCl 244 3 H H 0 Me H 0 Me 2HCl 245 3 H H 0 Me Me 0 Et 2HCl 246 3 H H 0 Et H 0 ^(n)Pr 2HCl 247 3 H H 0 Et Et 0 CHO HCl 248 3 H H 0 —CH₂CH₂— 0 Ac 2HCl 249 3 H H 0 —CH₂CH₂CH₂— 0 Bz 2HCl 250 3 H H 0 —CH₂(CH₂)₂CH₂— 0 CO₂Et HCl 251 3 H H 0 H H 0 CO₂ ^(n)Pr HCl 252 3 H H 0 H H 0 CO₂ ^(t)Bu HCl 253 3 H H 0 CH₂CH₂F CH₂CH₂F 0 H HCl 254 3 H H 0 CH₂CH₂Cl CH₂CH₂Cl 0 H HCl 255 3 H H 0 CH₂CH₂Br CH₂CH₂Br 0 H HCl ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 18

Substitution Ex. No. A T R₆ position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 256 (5) CR₆ NO₂ 2 4-H 5-Me H 2-H 4-OMe 5-H 6-H 257 (5) CR₆ NO₂ 2 4-H 5-Et H 2-H 4-OEt 5-H 6-H 258 (5) CR₆ NO₂ 2 4-H 5-^(n)Pr Me 2-H 4-O^(n)Pr 5-H 6-H 259 (5) CR₆ NO₂ 2 4-H 5-^(i)Pr H 2-H 4-O^(i)Pr 5-H 6-H 260 (5) CR₆ CO₂H 2 4-H 5-OMe H 2-Me 4-H 5-H 6-H 261 (5) CR₆ CO₂H 2 4-H 5-OEt H 2-Et 4-H 5-H 6-H 262 (5) CR₆ CO₂H 2 4-H 5-O^(n)Pr Et 2-^(n)Pr 4-H 5-H 6-H 263 (5) CR₆ CO₂Me 2 4-H 5-SMe H 2-H 4-H 5-NO₂ 6-H 264 (5) CR₆ CO₂Et 2 4-H 5-SEt H 2-H 4-H 5-NO₂ 6-H 265 (5) CR₆ CO₂ ^(n)Pr 2 4-H 5-S^(n)Pr ^(n)Pr 2-H 4-H 5-NO₂ 6-H 266 (5) CR₆ CN 2 4-H 5-H H 2-H 4-H 5-H 6-CO₂H 267 (5) CR₆ CN 2 4-H 5-H H 2-H 4-H 5-H 6-CO₂Me 268 (5) CR₆ CN 2 4-H 5-H H 2-H 4-H 5-H 6-CO₂Et 269 (5) CR₆ CF₃ 2 4-H 5-H H 2-H 4-NH₂ 5-H 6-H 270 (5) CR₆ CF₃ 2 4-H 5-H H 2-H 4-CONH₂ 5-H 6-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 256 3 Me H 0 H H 0 Me HCl 257 3 H H 0 Me H 0 H HCl 258 3 H H 0 H H 0 Et HCl 259 3 H H 0 H H 0 H HCl 260 3 Et H 0 H H 0 H HCl 261 3 H H 0 Et H 0 ^(n)Pr HCl 262 3 H H 0 H H 0 ^(i)Pr HCl 263 3 ^(n)Pr H 0 H H 0 H HCl 264 3 H H 0 ^(n)Pr H 0 H HCl 265 3 H H 0 H H 0 Ac HCl 266 3 —CH₂CH₂— 0 H H 0 H HCl 267 3 H H 0 —CH₂CH₂— 0 H HCl 268 3 H H 0 H H 0 Bz HCl 269 3 CH₂CH₂F H 0 H H 0 H 2HCl 270 3 H H 0 CH₂CH₂F H 0 CHO 2HCl ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 19

Substitution Ex. No. A T R₆ position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 271 (5) CR₆ H 4 2-CHO 5-H H 2-F 3-H 5-H 6-H 272 (5) CR₆ H 4 2-CHO 5-H H 2-Cl 3-H 5-H 6-H 273 (5) CR₆ H 4 2-H 5-NHAc Ac 2-Br 3-H 5-H 6-H 274 (5) CR₆ H 4 2-H 5-NHBz H 2-H 3-H 5-H 6-H 275 (5) CR₆ H 4 2-CONH₂ 5-H H 2-H 3-H 5-H 6-H 276 (5) CR₆ H 4 2-CONHMe 5-H Bz 2-H 3-H 5-H 6-H 277 (5) CR₆ H 4 2-H 5-CONHEt H 2-H 3-H 4-H 5-H 278 (5) CR₆ H 4 2-H 5-CONH^(n)Pr H 2-H 3-H 4-H 5-H 279 (5) CR₆ H 4 2-F 5-H CO₂Me 2-H 3-NHAc 4-H 5-H 280 (5) CR₆ H 4 2-Cl 5-H H 2-H 3-NHBz 4-H 5-H 281 (5) CR₆ H 4 2-Br 5-H H 2-H 2-CONHMe 4-H 5-H 282 (5) CR₆ NHMe 4 2-H 5-H CO₂Et 2-H 3-H 4-H 5-H 283 (5) CR₆ NHEt 4 2-H 5-H H 2-H 3-H 4-H 5-H 284 (5) CR₆ NH^(n)Pr 4 2-H 5-H H 2-H 3-H 4-H 5-H 285 (5) CR₆ H 4 2-OH 5-H CO₂ ^(t)Bu 2-H 3-H 4-H 5-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 271 4 H H 1 H H 0 CO₂Me HCl 272 4 H H 1 H H 0 CO₂Et HCl 273 4 Ac H 1 H H 0 H 274 4 Bz H 1 H H 0 H 275 4 Me Me 1 H H 0 H 2HCl 276 4 H H 1 Me Me 0 H 2HCl 277 6 CO₂Et H 0 H H 1 H 278 6 H H 0 H H 1 H 2HCl 279 6 CO₂ ^(t)Bu H 0 H H 1 H 280 6 H H 0 H H 1 H 2HCl 281 6 H H 0 H H 1 H 2HCl 282 6 CH₂CH₂Cl CH₂CH₂Cl 0 H H 1 H HCl 283 6 H H 0 CH₂CH₂Br CH₂CH₂Br 1 H 2HCl 284 6 H H 0 H H 1 H 2HCl 285 6 H H 0 H H 1 H 2HCl ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 20

Substitution Ex. No. A T position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 286 (5) N 2 4-NO₂ 5-H Me 2-Me 4-H 5-H 6-H 287 (5) N 2 4-NO₂ 5-H H 2-Et 4-H 5-H 6-H 288 (5) N 2 4-CO₂H 5-H H 2-H 4-^(n)Pr 5-H 6-H 289 (5) N 2 4-CO₂H 5-H Et 2-H 4-^(i)Pr 5-H 6-H 290 (5) N 2 4-CF₃ 5-H H 2-H 4-H 5-OMe 6-H 291 (5) N 2 4-CF₃ 5-H H 2-H 4-H 5-OEt 6-H 292 (5) N 2 4-CO₂Me 5-H ^(n)Pr 2-H 4-H 5-H 6-NHMe 293 (5) N 2 4-CO₂Me 5-H H 2-H 4-H 5-H 6-NHEt 294 (5) N 2 4-CO₂Et 5-H H 2-SMe 4-H 5-H 6-H 295 (5) N 2 4-CO₂Et 5-H ^(i)Pr 2-SEt 4-H 5-H 6-H 296 (5) N 2 4-CN 5-H H 2-H 4-OH 5-H 6-H 297 (5) N 2 4-CN 5-H H 2-H 4-F 5-H 6-H 298 (5) N 2 4-NH₂ 5-H Ac 2-H 4-H 5-Cl 6-H 299 (5) N 2 4-NHAc 5-H H 2-H 4-H 5-Br 6-H 300 (5) N 2 4-NHMe 5-H H 2-H 4-H 5-H 6-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 286 3 H H 0 Me H 0 H HCl 287 3 Me H 0 H H 0 Me HCl 288 3 H H 0 Et H 0 H HCl 289 3 Et H 0 H H 0 Et HCl 290 3 H H 0 ^(n)Pr H 0 H 2HCl 291 3 ^(n)Pr H 0 H H 0 Ac HCl 292 3 H H 0 H H 0 H 2HCl 293 3 —CH₂CH₂— 0 H H 0 Bz HCl 294 3 H H 0 —CH₂CH₂— 0 H HCl 295 3 Ac H 0 H H 0 H 296 3 H H 0 CH₂CH₂F H 0 H HCl 297 3 Bz H 0 H H 0 H 298 3 H H 0 H H 0 H 2HCl 299 3 CO₂ ^(t)Bu H 0 H H 0 H 300 3 H H 0 CH₂CH₂Cl H 0 H 2HCl ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 21

Substitution Ex. No. A T position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 301 (5) N 2 4-H 5-NMe₂ Bz 2-H 4-H 5-H 6-NO₂ 302 (5) N 2 4-H 5-NHEt H 2-H 4-H 5-H 6-NO₂ 303 (5) N 2 4-H 5-NH^(n)Pr H 2-H 4-H 5-CO₂H 6-H 304 (5) N 2 4-H 5-OH H 2-H 3-CO₂Me 5-H 6-H 305 (5) N 2 4-H 5-OMe H 2-H 3-CO₂Et 5-H 6-H 306 (5) N 2 4-H 5-OEt CO₂Me 2-H 3-H 5-CN 6-H 307 (5) N 2 4-H 5-Me H 2-H 3-H 5-H 6-CHO 308 (5) N 4 2-Me 5-H H 3-CONH₂ 4-H 5-H 6-H 309 (5) N 4 2-Et 5-H H 3-H 4-CONHMe 5-H 6-H 310 (5) N 4 2-^(n)Pr 5-H CO₂Et 3-CH₂OH 4-H 5-H 6-H 311 (5) N 4 2-H 5-SMe H 3-H 4-CH₂Cl 5-H 6-H 312 (5) N 4 2-H 5-SEt H 3-H 4-H 5-H 6-H 313 (5) N→O 2 4-Me 5-H H 2-H 4-H 5-H 6-NO₂ 314 (5) N→O 2 4-Et 5-H CO₂ ^(t)Bu 2-H 4-H 5-H 6-CHO 315 (5) N→O 2 4-^(n)Pt 5-H H 2-H 4-H 5-H 6-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 301 3 CH₂CH₂Cl CH₂CH₂Cl 0 H H 0 H 2HCl 302 3 H H 0 H H 0 H 2HCl 303 3 CH₂CH₂Br CH₂CH₂Br 0 H H 0 H 2HCl 304 4 H H 1 Me Me 0 CHO HCl 305 4 H H 1 Et Et 0 CO₂Me HCl 306 4 H H 0 H H 1 CO₂Et HCl 307 4 H H 0 H H 1 H 2HCl 308 2 CO₂ ^(t)Bu CO₂ ^(t)Bu 1 H H 0 H 309 2 H H 1 H H 0 H 2HCl 310 2 Me Me 0 H H 1 H 2HCl 311 2 H H 0 CH₂CH₂OH CH₂CH₂OH 1 H 2HCl 312 2 H H 0 H H 1 H 2HCl 313 3 H H 0 H H 0 H HCl 314 3 H H 0 H H 0 H HCl 315 3 H H 0 H H 0 H HCl ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 22

Substitution Ex. No. A U W position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 316 (4) N N 3 2-NO₂ 5-H 6-Me 2-H 4-H 5-H 6-H 317 (4) N N 3 2-NO₂ 5-H 6-H 2-Me 4-H 5-H 6-H 318 (4) N N 3 2-CO₂H 5-H 6-Et 2-H 4-OMe 5-H 6-H 319 (4) N N 3 2-CO₂H 5-H 6-H 2-Et 4-H 5-H 6-H 320 (4) N N 3 2-CO₂Me 5-H 6-^(n)Pr 2-H 4-OEt 5-H 6-H 321 (4) N N 3 2-CO₂Et 5-H 6-H 2-^(n)Pr 4-H 5-H 6-H 322 (4) N N 3 2-CO₂ ^(n)Pr 5-H 6-^(n)Bu 2-H 4-O^(n)Pr 5-H 6-H 323 (4) N N 3 2-CN 5-H 6-OH 2-H 4-H 5-H 6-H 324 (4) N N 3 2-CN 5-H 6-H 2-H 4-H 5-NH₂ 6-H 325 (4) N N 3 2-H 5-NH₂ 6-H 2-H 4-H 5-NHMe 6-H 326 (4) N N 3 2-H 5-NHAc 6-H 2-H 4-H 5-NHEt 6-H 327 (4) N N 3 2-H 5-NHBz 6-H 2-H 4-SMe 5-H 6-H 328 (4) N N 3 2-CONH₂ 5-H 6-H 2-H 4-SEt 5-H 6-H 329 (4) N N 3 2-CONHMe 5-H 6-H 2-H 4-H 5-H 6-H 330 (4) N N 3 2-H 5-H 6-Me 2-H 4-H 5-H 6-NO₂ Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 316 3 CO₂ ^(t)Bu H 0 H H 0 H 317 3 H Me 0 H H 0 H HCl 318 3 Ac H 0 H H 0 H 319 3 H Et 0 H H 0 H HCl 320 3 Bz H 0 H H 0 H 321 3 H ^(n)Pr 0 H H 0 H HCl 322 3 H H 0 Me H 0 H HCl 323 3 H H 0 H H 0 H HCl 324 3 H H 0 Et H 0 H 2HCl 325 3 H H 0 H H 0 H 2HCl 326 3 H H 0 CH₂CH₂Cl CH₂CH₂Cl 0 H 2HCl 327 3 H H 0 H H 0 H 2HCl 328 3 CO₂Me H 0 H H 0 H 329 3 CH₂CH₂Br CH₂CH₂Br 0 H H 0 H 2HCl 330 3 H H 0 CH₂OH H 0 H 2HCl ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 23

Substitution Ex. No. A U W position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 331 (4) N N 3 2-H 5-H 6-Et 2-H 3-H 5-H 6-CO₂H 332 (4) N N 3 2-H 5-H 6-^(n)Pr 2-H 3-H 5-H 6-CO₂Me 333 (4) N N 3 2-H 5-H 6-^(n)Bu 2-H 3-H 5-H 6-CO₂Et 334 (4) N N 3 2-H 5-OH 6-H 2-H 3-H 5-CN 6-H 335 (4) N N 3 2-H 5-OMe 6-H 2-H 3-H 5-F 6-H 336 (4) N N 3 2-H 5-OEt 6-H 2-H 3-H 5-H 6-CO₂NH₂ 337 (4) N N 3 2-SMe 5-H 6-H 2-Cl 3-H 4-H 5-H 338 (4) N N 3 2-Et 5-H 6-H 2-CH₂OH 3-H 4-H 5-H 339 (4) N N 3 2-CF₃ 5-H 6-H 2-H 3-H 4-H 5-CO₂NHMe 340 (4) N N 3 2-CF₃ 5-H 6-H 2-H 3-H 4-H 5-cyclopentyl 341 (4) N N 3 2-H 5-H 6-pyrrolidin-1-yl 2-H 3-H 4-H 5-H 342 (4) N N 3 2-H 5-H 6-piparidino 2-H 3-H 4-H 5-H 343 (4) N→I N→I 3 2-H 5-H 6-cyclobutyl 2-H 4-H 5-H 6-H 344 (4) N→I N→I 3 2-H 5-H 6-H 2-H 3-H 5-H 6-cyclohexylthio 345 (4) N→I N→I 3 2-H 5-H 6-H 2-H 3-H 4-Bn 5-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 331 4 Me Me 1 H H 0 Me 2HCl 332 4 H H 1 H H 0 H 2HCl 333 4 H H 1 H H 0 Et 2HCl 334 4 H H 0 Me Me 1 H 2HCl 335 4 H H 0 H H 1 ^(n)Pr 2HCl 336 4 H H 0 H H 1 H 2HCl 337 6 H H 0 H H 1 Ac HCl 338 6 H H 0 H H 1 H 2HCl 339 6 H H 0 H H 1 Bz HCl 340 6 H H 1 H H 0 H 2HCl 341 6 H H 1 H H 0 CO₂ ^(i)Bu — 342 6 H H 1 H H 0 H 2HCl 343 3 H H 0 H H 0 H 2HCl 344 4 H H 1 H H 0 H 2HCl 345 6 H H 0 H H 1 H 2HCl ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 24

Substitution Ex. No. A U W position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 346 (3) N N 3 4-NO₂ 5-H 6-H 2-Me 4-H 5-H 6-H 347 (3) N N 3 4-NO₂ 5-H 6-H 2-Et 4-H 5-H 6-H 348 (3) N N 3 4-H 5-CO₂H 6-H 2-H 4-^(n)Bu 5-H 6-H 349 (3) N N 3 4-H 5-CO₂Me 6-H 2-H 4-Bn 5-H 6-H 350 (3) N N 3 4-H 5-H 6-CONH₂ 2-H 4-H 5-NH₂ 6-H 351 (3) N N 3 4-H 5-H 6-CONHMe 2-H 4-H 5-NHMe 6-H 352 (3) N N 3 4-CF₃ 5-H 6-H 2-F 4-H 5-H 6-H 353 (3) N N 3 4-CF₃ 5-H 6-H 2-H 4-Br 5-H 6-H 354 (3) N N 3 4-H 5-CN 6-H 2-Cl 4-H 5-H 6-H 355 (3) N N 3 4-H 5-CN 6-H 2-H 4-NHBn 5-H 6-H 356 (3) N N 3 4-NH₂ 5-H 6-H 2-H 4-OMe 5-H 6-H 357 (3) N N 3 4-H 5-NHMe 6-H 2-H 4-H 5-OEt 6-H 358 (3) N N 3 4-H 5-H 6-NHBn 2-^(n)Pr 4-H 5-H 6-H 359 (3) N N 3 4-^(n)Pr 5-H 6-H 2-H 4-H 5-H 6-NO₂ 360 (3) N N 3 4-H 5-Et 6-H 2-H 4-H 5-H 6-CHO Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 346 3 Me H 0 H H 0 H HCl 347 3 H H 0 H H 0 Me HCl 348 3 Et H 0 H H 0 H HCl 349 3 H H 0 H H 0 Et HCl 350 3 Bn H 0 H H 0 H 351 3 H H 0 H H 0 Ac HCl 352 3 H H 0 Me Me 0 H 2HCl 353 3 H H 0 H H 0 H 2HCl 354 3 H H 0 Me H 0 H HCl 355 3 H H 0 H H 0 H HCl 356 3 Ac H 0 H H 0 H — 357 3 H H 0 H H 0 Bz 2HCl 358 3 CO₂Me H 0 H H 0 H 359 3 H H 0 H H 0 H 2HCl 360 3 CO₂ ^(t)Bu H 0 H H 0 H ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 25

Substitution Ex. No. A U W position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 361 (3) N N 3 4-Me 5-H 6-H 2-H 4-CO₂H 5-H 6-H 362 (3) N N 3 4-SMe 5-H 6-H 2-H 4-H 5-CO₂Et 6-H 363 (3) N N 3 4-H 5-SEt 6-H 2-H 4-H 5-H 6-CONH₂ 364 (3) N N 3 4-H 5-H 6-S^(n)Pr 2-H 4-H 5-CONHMe 6-H 365 (3) N N 3 4-F 5-H 6-H 2-CN 3-H 5-pyrrolidin-1-yl 6-H 366 (3) N N 3 4-H 5-Br 6-H 2-H 3-H 5-piperidino 6-H 367 (3) N→O N→O 3 4-H 5-H 6-Me 2-H 3-H 5-H 6-H 368 (3) N→O N→O 3 4-H 5-H 6-H 2-H 4-H 5-H 6-H 369 (3) N N 4 3-OMe 5-H 6-H 2-F 4-H 5-H 6-H 370 (3) N N 4 3-H 5-OEt 6-H 2-H 3-Cl 5-H 6-H 371 (3) N N 4 3-H 5-H 5-O^(n)Pr 2-H 3-H 5-Br 6-H 372 (3) N N 4 3-NO₂ 5-H 6-OMe 2-H 3-H 4-CH₂CH₂Ph 5-H 373 (3) N N 4 3-H 5-H 6-H 2-H 3-H 4-CH₂(CH₂)₂Ph 5-H 374 (3) N→O N→O 4 3-H 5-H 6-NHMe 2-H 3-H 4-H 5-H 375 (3) N→O N→O 4 3-H 5-H 6-NHEt 2-H 3-H 5-H 6-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 361 3 H H 0 H H 0 H HCl 362 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 CO₂ ^(t)Bu 363 3 H H 0 H H 0 H 2HCl 364 3 H H 0 H H 0 H 2HCl 365 4 H H 1 H H 0 Me 2HCl 366 4 H H 0 H H 1 H 2HCl 367 4 H H 1 H H 0 H HCl 368 3 H H 0 H H 0 H HCl 369 3 Et H 0 H H 0 H 2HCl 370 3 H H 0 Et H 0 H 2HCl 371 3 H H 0 H H 0 H 2HCl 372 6 H H 1 H H 0 H HCl 373 6 H H 1 CH₂OH H 0 H 2HCl 374 6 H H 0 H H 1 CO₂Et 2HCl 375 3 H H 0 H H 1 H 2HCl ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 26

Substitution Ex. No. A T position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 376 (6) N 3 4-NO₂ 5-H H 2-H 4-Me 5-H 6-H 377 (6) N 3 4-NO₂ 5-H Me 2-H 4-Et 5-H 6-H 378 (6) N 3 4-CF₃ 5-H H 2-H 4-^(n)Pr 5-H 6-H 379 (6) N 3 4-CF₃ 5-H Et 2-CH₂OH 4-H 5-H 6-H 380 (6) N 3 4-H 5-CO₂H H 2-CH₂CH₂OH 4-H 5-H 6-H 381 (6) N 3 4-H 5-CO₂Me ^(n)Pr 2-H 4-H 5-H 6-H 382 (6) N 3 4-H 5-CO₂Et H 2-H 4-H 5-NH₂ 6-H 383 (6) N 3 4-CN 5-H H 2-H 4-H 5-H 6-NHMe 384 (6) N 3 4-CONH₂ 5-H H 2-NHEt 4-H 5-H 6-H 385 (6) N 3 4-CONHMe 5-H H 2-H 4-H 5-H 6-H 386 (6) N 3 4-H 5-H Ac 2-Cl 4-H 5-H 6-H 387 (6) N 3 4-H 5-H Bn 2-Br 4-H 5-H 6-H 388 (6) N 3 4-H 5-H CO₂Me 2-OMe 4-H 5-H 6-H 389 (6) N 3 4-H 5-H CO₂Et 2-H 4-OEt 5-H 6-H 390 (6) N 3 4-H 5-H CO₂ ^(n)Pr 2-H 4-OBn 5-H 6-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 376 3 Me H 0 H H 0 Me 2HCl 377 3 H H 0 Me Me 0 H 2HCl 378 3 H H 0 Me H 0 H HCl 379 3 Et H 0 H H 0 H HCl 380 3 H H 0 H H 0 Et HCl 381 3 H H 0 Et H 0 H HCl 382 3 ^(n)Pr H 0 H H 0 H 2HCl 383 3 H H 0 H H 0 Ac 2HCl 384 3 H H 0 CH₂OH H 0 H 2HCl 385 3 Ac H 0 H H 0 H 386 3 H H 0 CH₂CH₂OH CH₂CH₂OH 0 H HCl 387 3 H H 0 Et Et 0 H HCl 388 3 H H 0 H H 0 Bn HCl 389 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 390 3 H H 0 Bn H 0 Bz HCl ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 27

Substitution Ex. No. A T position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 391 (6) N 3 4-OMe 5-H Bz 2-H 4-H 5-H 6-NO₂ 392 (6) N 3 4-OEt 5-H H 2-H 4-H 5-H 6-CO₂Me 393 (6) N 3 4-O^(n)Pr 5-H H 2-H 4-H 5-H 6-CO₂Et 394 (6) N 3 4-H 5-SMe H 2-H 3-H 5-CONH₂ 6-H 395 (6) N 3 4-H 5-SEt H 2-H 3-H 5-CONHMe 6-H 396 (6) N 4 3-H 5-S^(n)Bu H 2-H 3-H 5-CONHEt 6-H 397 (6) N 4 3-F 5-H H 2-H 3-H 5-H 6-H 398 (6) N 4 3-Cl 5-H H 2-H 4-SMe 5-H 6-H 399 (6) N 4 3-Br 5-H H 2-H 4-SEt 5-H 6-H 400 (6) N 4 3-NH₂ 5-H H 2-H 3-H 4-H 5-CHO 401 (6) N 4 3-NHMe 5-H H 2-H 3-H 4-NHCO₂Me 5-H 402 (6) N→O 4 3-H 5-Me H 2-H 3-OBn 4-H 5-H 403 (6) N→O 4 3-H 5-Et H 2-H 4-H 5-H 6-H 404 (6) N→O 3 4-H 5-OMe H 2-H 4-NHBn 5-H 6-H 405 (6) N→O 3 4-H 5-OEt H 2-H 3-H 5-H 6-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ salt 391 3 H H 0 H H 0 H HCl 392 3 Me Me 0 H H 0 H 2HCl 393 3 H H 0 H H 0 CO₂Me 2HCl 394 4 H H 1 H H 0 H 2HCl 395 4 H H 1 H H 0 H 2HCl 396 4 H H 0 Me H 1 H 2HCl 397 4 CH₂CH₂Br CH₂CH₂Br 0 H H 1 H 2HCl 398 3 H H 0 H H 0 H 2HCl 399 3 H H 0 H H 0 H 2HCl 400 6 H H 1 H H 0 H 2HCl 401 6 H H 1 H H 0 H 2HCl 402 6 —CH₂(CH₂)₂CH₂— 1 H H 0 H HCl 403 3 H H 1 —CH₂(CH₂)₃CH₂— 0 H HCl 404 3 H H 1 H H 0 H 2HCl 405 4 H H 1 H H 0 H HCl ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 28

Substitution Ex. No. A Y Z R₆ position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 406 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-Me 4-H 5-H 6-H 407 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-pyrrolidin-1-yl 5-H 6-H 408 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 3-H 5-H 6-H 409 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-OMe 410 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 411 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-Me 6-H 412 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 3-H 4-H 5-H 6-H 413 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-OMe 4-H 5-H 6-H 414 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-Cl 5-H 6-H 415 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-Me 5-H 6-H 416 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-F 5-H 6-H 417 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-OEt 4-H 5-H 6-H 418 (2) CR₆ CH NO₂ 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-H 419 (2) CR₆ CH NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 420 (2) CR₆ CH NO₂ 2 4-H 5-H 6-OMe 2-H 4-OMe 5-H 6-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ 406 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 407 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 408 4 CO₂ ^(t)Bu H 1 H H 0 H 409 3 CO₂ ^(t)Bu H 0 H H 0 H 410 3 CO₂ ^(t)Bu H 0 Me Me 0 H 411 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 412 2 CO₂ ^(t)Bu H 1 H H 0 H 413 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 414 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 415 3 CO₂ ^(t)Bu H 0 H H 0 H 416 3 CO₂ ^(t)Bu H 0 H H 0 H 417 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 418 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 419 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 420 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 29

Substitution Ex. No. A Y Z R₆ position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 421 (2) CR₆ N H 2 4-H 5-NO₂ 6-OMe 2-H 4-H 5-H 6-H 422 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 423 (2) CR₆ N H 2 4-CO₂Me 5-H 6-H 2-H 4-H 5-H 6-H 424 (2) CR₆ N — 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 425 (2) CR₆ N NO₂ 2 4-H 5-H 6-OEt 2-H 4-H 5-H 6-H 426 (2) CR₆ N CF₃ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 427 (2) CR₆ CH NO₂ 2 4-H 5-OMe 6-H 2-H 4-H 5-H 6-H 428 (2) CR₆ CMe NO₂ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 429 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 430 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 431 (2) CR₆ N H 2 4-Me 5-H 6-H 2-Me 4-H 5-H 6-H 432 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-Et 5-H 6-H 433 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-OEt 5-H 6-H 434 (2) CR₆ N H 2 4-Me 5-H 6-H 3-H 4-H 5-H 6-H 435 (2) CR₆ N H 2 4-Me 5-H 6-H 2-Cl 4-H 5-H 6-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ 421 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 422 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 423 3 CO₂ ^(t)Bu H 0 H H 0 H 424 3 CO₂ ^(t)Bu H 0 H H 0 H 425 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 426 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 427 3 CO₂ ^(t)Bu H 0 H H 0 H 428 3 CO₂ ^(t)Bu H 0 H H 0 H 429 3 CO₂ ^(t)Bu H 0 Me Me 0 H 430 3 CO₂ ^(t)Bu H 0 Et H 0 H 431 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 432 3 CO₂ ^(t)Bu H 0 H H 0 H 433 3 CO₂ ^(t)Bu H 0 H H 0 H 434 2 CO₂ ^(t)Bu H 1 H H 0 H 435 3 CO₂ ^(t)Bu H 0 H H 0 H ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 30

Substitution Ex. No. A Y Z R₆ position of A R₇ ^(*1) R₈ ^(*1) R₉ ^(*1) X₁ ^(*2) X₂ ^(*2) X₃ ^(*2) X₄ ^(*2) 436 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 437 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 3-H 5-H 6-H 438 (2) CR₆ N H 2 4-Me 5-H 6-H 2-OEt 4-H 5-H 6-H 439 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-Cl 5-H 6-H 440 (2) CR₆ N CN 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 441 (2) CR₆ N Cl 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 442 (2) CR₆ N CO₂Me 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 443 (2) CR₆ N H 2 4-CO₂H 5-H 6-OMe 2-H 4-H 5-H 6-H 444 (2) CR₆ N H 2 4-CH₂OH 5-H 6-OMe 2-H 4-H 5-H 6-H 445 (2) CR₆ N H 2 4-Me 5-H 6-OMe 2-H 4-H 5-H 6-H 446 (2) CR₆ N NO₂ 2 4-H 5-H 6-CH(CO₂Me)₂ 2-H 4-H 5-H 6-H 447 (2) CR₆ N NO₂ 2 4-H 5-H 6-CMe(CO₂Et)₂ 2-H 4-H 5-H 6-H 448 (2) CR₆ N NO₂ 2 4-H 5-H 6-SMe 2-H 4-H 5-H 6-H 449 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 450 (2) CR₆ N H 2 4-Me 5-H 6-Me 2-H 4-H 5-H 6-H Substitution Ex. No. position of W* R₁ R₂ n R₃ R₄ m R₅ 436 3 CO₂ ^(t)Bu H 0 —CH₂CH₂CH₂— 0 H 437 4 CO₂ ^(t)Bu H 1 H H 0 H 438 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 439 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 440 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 441 3 CO₂ ^(t)Bu H 0 H H 0 H 442 3 CO₂ ^(t)Bu H 0 H H 0 H 443 3 CO₂ ^(t)Bu H 0 H H 0 H 444 3 CO₂ ^(t)Bu H 0 H H 0 H 445 3 CO₂ ^(t)Bu H 0 H H 0 H 446 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 447 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 448 3 CO₂ ^(t)Bu H 0 H H 0 H 449 3 CO₂ ^(t)Bu H 0 H H 0 H 450 3 CO₂ ^(t)Bu H 0 H H 0 H ^(*1)Numerals represent substitution positions in the structural formulas of (2)-(7) employed. ^(*2)Numerals represent substitution positions on the benzene ring.

TABLE 31

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 451 (2) CR₆ N H 2 4-Et 5-H 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 452 (2) CR₆ N CO₂H 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 453 (2) CR₆ N CONH₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 454 (2) CR₆ N CH₂OH 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 455 (2) CR₆ N Me 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 456 (2) CR₆ N CHO 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 457 (2) CR₆ N H 2 4-H 5-NO₂ 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 458 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-Me 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 459 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-pyrrolidin-1-yl 5-H 6-H 3 H H 0 H H 0 H 2HCl 460 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 3-H 5-H 6-H 4 H H 1 H H 0 H HCl 461 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-OMe 3 H H 0 H H 0 H HCl 462 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 Me Me 0 H HCl 463 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-Me 6-H 3 H H 0 H H 0 H HCl 464 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 3-H 4-H 5-H 6-H 2 H H 1 H H 0 H HCl 465 (2) CR₆ N NO₂ 2 A-H 5-H 6-OMe 2-OMe 4-H 5-H 6-H 3 H H 0 H H 0 H HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 32

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 466 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-Cl 5-H 6-H 3 H H 0 H H 0 H HCl 467 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-H 4-F 5-H 6-H 3 H H 0 H H 0 H HCl 468 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-OEt 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 469 (2) CR₆ N NO₂ 2 4-H 5-H 6-OMe 2-Cl 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 470 (2) CR₆ N H 2 4-CO₂Me 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 471 (2) CR₆ N H 2 4-CO₂H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H O H H 0 H HCl 472 (2) CR₆ N H 2 4-CH₂OH 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 473 (2) CR₆ N H 2 4-Me 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 474 (2) N N — 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 475 (2) CR₆ N CF₃ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 476 (2) CR₆ CH NO₂ 2 4-H 5-OMe 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 477 (2) CR₆ CMe NO₂ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 478 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 6 H 2HCl 479 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 Me Me 0 H 2HCl 480 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 Et H 0 H 2HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 33

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 481 (2) CR₆ N H 2 4-Me 5-H 6-H 2-Me 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 482 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-Et 5-H 6-H 3 H H 0 H H 0 H 2HCl 483 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-OEt 5-H 6-H 3 H H 0 H H 0 H 2HCl 484 (2) CR₆ N H 2 4-Me 5-H 6-H 3-H 4-H 5-H 6-H 2 H H 1 H H 0 H 2HCl 485 (2) CR₆ N H 2 4-Me 5-H 6-H 2-Cl 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 486 (2) CR₆ N H 2 4-Me 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 487 (2) CR₆ N H 2 4-Et 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 488 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 —CH₂CH₂CH₂— 0 H 2HCl 489 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 3-H 5-H 6-H 4 H H 1 H H 0 H 2HCl 490 (2) CR₆ N H 2 4-Me 5-H 6-H 2-OEt 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 491 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-Cl 5-H 6-H 3 H H 0 H H 0 H 2HCl 492 (2) CR₆ N CN 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 493 (2) CR₆ N Cl 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 494 (2) CR₆ N CONH₂ 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H HCl 495 (2) CR₆ N Me 2 4-H 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 34

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 496 (2) CR₆ CH NO₂ 2 4-H 5-H 6-OMe 2-H 4-OMe 5-H 6-H 3 H H 0 H H 0 H HCl 497 (2) CR₆ N H 2 4-H 5-Me 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 498 (2) CR₆ N Me 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 499 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-OMe 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 500 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-pyrazol-1-yl 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 501 (2) CR₆ N H 2 4-H 5-Me 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 502 (2) CR₆ N Me 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 503 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-OMe 5-H 6-H 3 H H 0 H H 0 H 2HCl 504 (2) CR₆ N H 2 4-Me 5-H 6-H 2-H 4-pyrazol-1-yl 5-H 6-H 3 H H 0 H H 0 H 2HCl 505 (2) CR₆ N H 2 4-Me 5-H 6-H 2-O^(n)Pr 4-H 5-H 6-H 3 CO₂ ^(t)Bu Co₂ ^(t)Bu 0 H H 0 H 506 (2) CR₆ N H 2 4-Me 5-H 6-H 2-O^(n)Pr 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl Substitution Substitution Ex. No. A T Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 507 (7) S — — 2 4-H 5-Me — 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 508 (7) S — — 2 4-H 5-Me — 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 509 (7) S — — 2 4-Me 5-H — 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 510 (7) S — — 2 4-Me 5-H — 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 35

Substitution Substitution Ex. No. A T Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 511 (7) O — — 2 4-H 5-Me — 2-H 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 512 (7) O — — 2 4-H 5-Me — 2-OEt 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 513 (7) O — — 2 4-H 5-Me — 2-Me 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 514 (7) O — — 2 4-H 5-Me — 2-H 4-OMe 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 515 (7) O — — 2 4-H 5-Me — 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H CF₃CO₂H 516 (7) O — — 2 4-H 5-Me — 2-OEt 4-H 5-H 6-H 3 H H 0 H H 0 H CF₃CO₂H 517 (7) O — — 2 4-H 5-Me — 2-Me 4-H 5-H 6-H 3 H H 0 H H 0 H CF₃CO₂H 518 (7) O — — 2 4-H 5-Me — 2-H 4-OMe 5-H 6-H 3 H H 0 H H 0 H CF₃CO₂H Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 519 (2) CR₆ N H 2 4-Me 5-H 6-H 2-OEt 4-Cl 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 520 (2) CR₆ N H 2 4-Me 5-H 6-H 2-OEt 4-Me 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 521 (2) CR₆ N H 2 4-Me 5-H 6-H 2-OEt 4-Cl 5-H 6-H 3 H H 0 H H 0 H 2HCl 522 (2) CR₆ N H 2 4-Me 5-H 6-H 2-OEt 4-Me 5-H 6-H 3 H H 0 H H 0 H 2HCl 523 (2) CR₆ N NO₂ 2 4-H 5-NO₂ 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 524 (2) CR₆ N CN 2 4-Me 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 525 (2) CR₆ N H 2 4-CN 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 36

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 526 (2) CR₆ N H 2 4-H 5-CN 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 527 (2) CR₆ N CN 2 4-CO₂Et 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 528 (2) CR₆ N H 2 4-CO₂H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 529 (2) CR₆ N H 2 4-H 5-CO₂H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 530 (2) CR₆ N Cl 2 4-H 5-CO₂H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 531 (2) CR₆ N H 2 4-CO₂H 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 532 (2) CR₆ N H 2 4-H 5-H 6-CO₂H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 533 (2) CR₆ N CONH₂ 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 534 (2) CR₆ N CONH₂ 2 4-H 5-Cl 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 535 (2) CR₆ N H 2 4-CONH₂ 5-H 6-OMe 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 536 (2) CR₆ N CONH₂ 2 4-H 5-H 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 537 (2) CR₆ N H 2 4-H 5-Br 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 538 (2) CR₆ N Cl 2 4-H 5-Cl 6-H 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 539 (2) CR₆ N H 2 4-H 5-H 6-Me 2-H 4-H 5-H 6-H 3 H H 0 H H 0 H 540 (2) CR₆ N H 2 4-Me 5-H 6-H 2-OMe 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

TABLE 37

Substitution Substitution Ex. No. A Y Z R₆ position of A R₇*¹ R₈*¹ R₉*¹ X₁*² X₂*² X₃*² X₄*² position of W* R₁ R₂ n R₃ R₄ m R₅ salt 541 (2) CR₆ N H 2 4-Me 5-H 6-H 2-OMe 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 542 (2) CR₆ N H 2 4-Me 5-H 6-H 2-O^(i)Pr 4-H 5-H 6-H 3 CO₂ ^(t)Bu CO₂ ^(t)Bu 0 H H 0 H 543 (2) CR₆ N H 2 4-Me 5-H 6-H 2-O^(i)Pr 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 544 (2) CR₆ N H 2 4-Me 5-H 6-H 2-O^(n)Bu 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 545 (2) CR₆ N H 2 4-Me 5-H 6-H 2-O^(n)Bu 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 546 (2) CR₆ N H 2 4-Me 5-H 6-H 2-O^(t)Bu 4-H 5-H 6-H 3 CO₂ ^(t)Bu H 0 H H 0 H 547 (2) CR₆ N H 2 4-Me 5-H 6-H 2-O^(t)Bu 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 548 (2) CR₆ N H 2 4-Me 5-H 6-H 2-OCH₂Ph 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 549 (2) CR₆ N H 2 4-Me 5-H 6-H 2-OCH₂CH₂Ph 4-H 5-H 6-H 3 H H o H H 0 H 2HCl 550 (2) CR₆ N H 2 4-Me 5-H 6-H 2-Et 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 551 (2) CR₆ N H 2 4-Me 5-H 6-H 2-CH₂Ph 4-H 5-H 6-H 3 H H 0 H H 0 H 2HCl 552 (2) CR₆ N H 2 4-Me 5-H 6-H 2-OMe 4-Me 5-H 6-H 3 H H 0 H H 0 H 2HCl 553 (2) CR₆ N H 2 4-Me 5-H 6-H 2-O^(i)Pr 4-Me 5-H 6-H 3 H H 0 H H 0 H 2HCl 554 (2) CR₆ N H 2 4-Me 5-H 6-H 2-O^(n)Bu 4-Me 5-H 6-H 3 H H 0 H H 0 H 2HCl 555 (2) CR₆ N H 2 4-Me 5-H 6-H 2-O^(t)Bu 4-Me 5-H 6-H 3 H H 0 H H 0 H 2HCl *¹:Numerals represent substitution positions in the structural formulas of (2)-(7) employed. *²:Numerals represent substitution positions on the benzene ring.

Example 1 Synthesis of 2-(3-(di-(t-butoxycarbonyl)aminomethyl)phenylamino) -3-nitropyridine

A mixture of 3-(di-(t-butoxycarbonyl)aminomethyl)aniline (1.50 g), triethylamine (2.0 ml), 2-chloro-3-nitropyridine (1.10 g) and anhydrous dimethylformamide (15 ml) was stirred at 60° C. for 20 h and, thereafter, ethyl acetate and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 1.42 g of the titled compound (yield, 69%).

¹H-NMR(CDCL₃) δ: 1.47(18H, s), 4.81(2H, s), 6.83(1H, dd, J=8.3, 4.3 Hz), 7.11(1H, d, J=7.9 Hz), 7.34(1H, dd, J=7.9, 7.9 Hz), 7.55-7.63 (2H, m), 8.47(1H, dd, J=4.3, 1.7 Hz), 8.53(1H, dd, J=8.3, 1.7 Hz), 10.11(1H, brs)

The procedure of Example 1 was repeated using corresponding aniline derivatives or corresponding halogenated derivatives to give the compounds shown in Tables 38-43 (under “Reaction condition” in the tables, base:(1) is triethylamine and base:(2) is diisopropylethylamine).

TABLE 38 Aniline Halogenated Reaction Example derivative derivative Product condition Spectral data 9

base: (1) ¹H—NMR(CDCl₃)δ1.47(18H, s), 4.80(2H, s), 6.77(1H, d, J= 9.2Hz), 7.16(1H, d, J=7.3Hz), 7.26-7.39(3H, m), 8.23(1H, dd, J=9.2, 2.6Hz), 9.08(1H, d, J=2.6Hz) 13

base: (1) ¹H—NMR(CDCl₃)δ1.46(18H, s), 2.57(3H, s), 4.79(2H, s), 6.66(1H, d, J=5.0Hz), 7.06(1H, d, J=7.6Hz), 7.26-7.33(1H, m), 7.33(1H, dd, J=7.6, 7.6Hz), 7.46(1H, s), 8.18(1H, dd, J= 5.0Hz), 9.14(1H, brs) 17

base: (1) ¹H—NMR(CDCl₃)δ1.46(18H, s), 3.96(3H, s), 4.80(2H, s), 6.23(1H, d, J=9.2Hz), 7.10(1H, d, 8.6Hz), 7.32(1H, dd, J= 7.6, 7.6Hz), 7.56(1H, d, J=7.6Hz), 7.60(1H, s), 8.42(1H, d, J=9.2Hz), 10.63(1H, brs) 21

base: (1) ¹H—NMR(CDCl₃)δ1.45(18H, s), 3.85(3H, s), 3.90(3H, s), 4.84(2H, s), 6.17(1H, d, J=9.2Hz), 6.85(1H, d, J=8.6Hz), 7. 34(1H, d, J=2.3Hz), 7.46(1H, dd, J=8.6, 2.3Hz), 8.39(1H, d, J=9.2Hz), 10.50(1H, brs)

TABLE 39 Aniline Halogenated Reaction Example derivative derivative Product condition Spectral data 23

base: (1) ¹H—NMR(CDCl₃)δ1.24(3H, t, J=7.3Hz), 1.45(18H, s), 2.69( 2H, q, J=7.3Hz), 3.94(3H, s), 4.85(2H, s), 6.19(1H, d, J=8.9 Hz), 7.18(1H, d, J=8.3Hz), 7.32(1H, d, J=2.0Hz), 7.54(1H, dd, J=8.3, 2.0Hz), 8.40(1H, d, J=8.9Hz) 25

base: (1) ¹H—NMR(CDCl₃)δ1.30(3H, t, J=7.3Hz), 1.30(9H, s), 2.85( 2H, q, J=7.3Hz), 3.59(4H, s), 3.92(3H, s), 5.07(1h, brs), 6.18(1H, d, J=8.9Hz), 7.18-7.29(5H, m), 7.43(1H, s), 7.73( 1H, dd, J=8.6, 2.0Hz), 8.40(1H, d, J=8.9Hz), 10.58(1H, brs) 27

base: (1) ¹H—NMR(CDCl₃)δ10.33(1H, brs), 8.40(1H, d, J=8.9Hz), 7.61 1.47(18H, s), 4.81(2H, s), 6.80(1H, d, J= 8.6Hz), 7.13(1H, d, J=7.6Hz), 7.36(1H, dd, J=7.6, 7.6Hz), 7.49(1H, s), 7.65(1H, d, J=7.6Hz), 8.46(1H, d, J=8.6Hz), 10.24(1H, brs) 406

base: (1) ¹H—NMR(CDCl₃)δ10.33(1H, brs), 8.40(1H, d, J=8.9Hz), 7.61 (1H, d, J=7.9Hz), 7.21(1H, dd, J=7.9, 7.6Hz), 7.05(1H, d, J= 7.6Hz), 6.18(1H, d, J=8.9Hz), 4.85(2H, s), 3.76(3H, s), 2.27(3H, s), 1.45(18H, s) FAB—MS(m/z) 489(M* + 1)

TABLE 40 Aniline Halogenated Reaction Example derivative derivative Product condition Spectral data 407

base: (1) ¹H—NMR(CDCl₃)δ10.54(1H, brs), 8.39(1H, d, J=9.2Hz), 7.45 (1H, dd, J=8.6, 2.3Hz), 7.30-7.24(1H, m), 6.98(1H, d, J=8.6Hz), 6.16(1H, d, J=9.2Hz), 4.85(2H, s), 3.92(3H, s), 3.10(4H, t, J=5.4Hz), 1.94(4H, t, J=5.4Hz), 1.41(18H, s) FAB—MS(m/z) 544(M* + 1) 408

base: (1) ¹H—NMR(CDCl₃)δ10.62(1H, brs), 8.42(1H, d, J=8.9Hz), 7.60 (2H, d, J=8.6Hz), 7.21(2H, d, J=8.6Hz), 6.22(1H, d, J=8.9Hz ), 4.57(1H, brs), 3.96(3H, s), 3.39(2H, dt, J=6.9, 6.9Hz), 2.81(2H, t, J=6.9Hz), 1.44(9H, s) FAB—MS(m/z) 389(M* + 1) 409

base: (1) ¹H—NMR(CDCl₃)δ11.20(1H, brs), 8.56(1H, d, J=2.0Hz), 8.44 (1H, d, J=9.2Hz), 7.00(1H, dd, J=8.3, 2.0Hz), 6.90(1H, d, J= 8.3Hz), 6.23(1H, d, J=9.2Hz), 4.75(1H, brs), 4.29(2H, d, J= 5.6Hz), 4.06(3H, s), 3.96(3H, s), 1.46(9H, s) FAB—MS(m/z 405(M* + 1) 410

base: (1) ¹H—NMR(CDCl₃)δ10.68(1H, brs), 8.41(1H, d, J=8.9Hz), 7.65 (1H, s), 7.58(1H, t, J=7.9Hz), 7.33(1H, t, J=7.9Hz), 7.22(1 H, d, J=7.9Hz), 6.22(1H, d, J=8.9Hz), 4.97(1H, s), 3.98(3H, s), 1.65(9H, s), 1.38(6H, brs) FAB—MS(m/z) 403(M* + 1)

TABLE 41 Aniline Halogenated Reaction Example derivative derivative Product condition Spectral data 411

base: (1) ¹H—NMR(CDCl₃)δ10.60(1H, br), 8.40(1H, d, J=8.9Hz), 7.44( 1H, s), 7.37(1H, s), 6.92(1H, s), 6.21(1H, d, J=8.9Hz), 4.76 (2H, s), 3.97(3H, s), 2.35(3H, s), 1.46(18H, s) FAB—MS(m/z) 489(M* + 1) 412

base: (1) ¹H—NMR(CDCl₃)δ10.45(1H, brs), 8.41(1H, d, J=9.2Hz), 7.83 (1H, d, J=7.3Hz), 7.31-7.25(2H, m), 7.21(1H, d, J=7.3Hz), 6.20(1H, d, J=9.2Hz), 4.67(1H, brs), 3.81(3H, s), 3.39(2H, dt, J=6.9, 6.9Hz), 2.89(2H, t, J=6.9Hz), 1.39(9H, s) FAB—MS(m/z) 389(M* + 1) 413

base: (1) ¹H—NMR(CDCl₃)δ11.24(1H, brs), 8.45(1H, d, J=9.2Hz), 8.42 (1H, d, J=7.9Hz), 7.12(1H, dd, J=7.9, 7.6Hz), 6.95(1H, d, J= 7.6Hz), 6.26(1H, d, J=9.2Hz), 4.94(2H, s), 4.04(3H, s), 3.87(3H, s), 1.46(18H, s) FAB—MS(m/z) 505(M* + 1) 414

base: (1) ¹H—NMR(CDCl₃)δ10.59(1H, brs), 8.41(1H, d, J=9.2Hz), 7.54 (1H, dd, J=8.6, 2.3Hz), 7.39(1H, d, J=2.3Hz), 7.35(1H, d, J= 8.6Hz), 6.24(1H, d, J=9.2Hz), 4.93(2H, s), 3.94(3H, s), 1.45(18H, s)

TABLE 42 Aniline Halogenated Reaction Example derivative derivative Product condition Spectral data 415

base: (1) ¹H—NMR(CDCl₃)δ10.59(1H, brs), 8.40(1H, d, J=9.2Hz), 7.57 (1H, d, J=2.0Hz), 7.46(1H, dd, J=7.9, 2.0Hz), 7.11(1H, d, J= 7.9Hz), 6.21(1H, d, J=9.2Hz), 4.75(1H, brs), 4.33(2H, s, J= 5.6Hz), 3.96(3H, s), 2.32(3H, s), 1.47(9H, s) 416

base: (1) ¹ H—NMR(CDCl₃)δ10.53(1H, brs), 8.41(1H, d, J=9.2Hz), 7.67 (1H, d, J=8.9Hz), 7.52-7.43(1H, m), 7.05(1H, dd, J=9.2, 8.9 Hz), 6.23(1H, d, J=9.2Hz), 4.92(1H, brs), 4.38(2H, d, J=6.3 Hz), 3.94(3H, s), 1.45(9H, s) 417

base: (1) ¹H—NMR(CDCl₃)δ11.24(1H, brs), 8.46(1H, d, J=8.9Hz), 8.43 (1H, d, J=7.9Hz), 7.11(1H, dd, J=8.3, 7.9Hz), 6.93(1H, d, J= 8.3Hz), 6.25(1H, d, J=8.9Hz), 4.93(2H, s), 4.04(3H, s), 3.96(2H, q, J=6.9Hz), 1.52(3H, t, J=6.9Hz), 1.45(18H, s) 418

base: (1) ¹H—NMR(CDCl₃)δ1.47(18H, s), 2.26(3H, s), 4.80(2H, s), 6.59(1H, d, J=8.6Hz), 6.97(1H, s), 7.14-7.21(3H, m), 7.36( 1H, dd, J=7.6, 7.6Hz), 8.10(1H, d, J=8.6Hz)

TABLE 43 Aniline Halogenated Reaction Example derivative derivative Product condition Spectral data 419

base: (1) ¹H—NMR(CDCl₃)δ1.46(18H, s), 3.74(3H, s), 4.79(2H, s), 6.34(1H, dd, J=9.6, 2.6Hz), 6.57(1H, dd, J=2.6Hz), 7.14- 7.20(2H, m), 7.24(1H, s), 7.37(1H, dd, J=7.6, 7.6Hz), 8.18( 1H, d, J=9.6Hz), 9.77(1H, brs) 420

base: (2) ¹H—NMR(CDCl₃)δ1.44(18H, s), 3.70(3H, s), 3.86(3H, s), 4.81(2H, s), 6.27(1H, dd, J=9.6, 2.6Hz), 6.33(1H, d, J=2.6 Hz), 6.89(1H, d, J=8.3Hz), 7.03(1H, d, J=2.0Hz), 7.11(1H, dd, J=8.3, 2.0Hz), 8.16(1H, d, J=9.6Hz), 9.66(1H, s)

Example 2 Synthesis of 2-(3-aminomethylphenylamino)-3-nitropyridine hydrochloride

A mixture of the compound (95.2 mg) obtained in Example 1 and trifluoroacetic acid (2 ml) was stirred at room temperature for 1 h and concentrated under reduced pressure. The resulting residue was dissolved in methanol (3 ml) and a 1,4-dioxane solution (4 N, 0.5 ml) of hydrogen chloride was added at room temperature and the mixture was concentrated under reduced pressure. In addition, the resulting residue was recrystallized from ethanol-ethyl acetate to give 56.7 mg of the titled compound (yield, 94%)

¹H-NMR(DMSO-d₆) δ: 4.03(2H, q, J=5.6 Hz), 7.03(1H, dd, J=8.2, 4.3 Hz), 7.28(1H, d, J=7.6 Hz), 7.42(1H, dd, J=7.6, 7.6 Hz), 7.74(1H, s), 7.75(1H, d, J=7.6 Hz), 8.46(3H, brs), 8.50-8.60(2H, m), 10.00(1H, s)

The procedure of Example 2 was repeated using corresponding reagents to give the compounds shown in Tables 44-62.

TABLE 44 Example Reagent Product Spectral data 4

¹H—NMR(DMSO-d₆)δ3.52(3H, brs), 4.03(2H, q, J=5.6Hz), 6.95(1H, dd, J=7.0, 7.0Hz), 7.28(1H, d, J=7.9Hz), 7.33-7.40(3H, m), 7.48(1H, d, J= 7.9Hz), 7.58(1H, s), 8.52(3H, brs), 10.22(1H, brs) 8

¹H—NMR(DMSO-d₆)δ1.30(3H, t, J=6.9Hz), 3.21(2H, q, J=6.9Hz), 4.04( 2H, q, J=6.9Hz), 7.01(1H, dd, J=7.9, 5.9Hz), 7.10(1H, d, J=7.3Hz), 7.35(1H, d, J=5.9Hz), 7.39(1H, dd, J=7.3, 7.3Hz), 7.41(1H, d, J=7.3Hz ), 7.50(1H, d, J=7.9Hz), 7.59(1H, s), 8.57(3H, brs), 10.55(1H, brs) 10

¹H—NMR(DMSO-d₆)δ4.01(2H, q, J=5.6Hz), 7.08(1H, d, J=9.6Hz), 7.23( 1H, d, J=7.6Hz), 7.41(1H, dd, J=7.6, 7.6Hz), 7.74(1H, d, J=7.6Hz), 7.85(1H, s), 8.31(1H, dd, J=9.6, 2.6Hz), 8.47(3H, brs), 9.04(1H, d, J= 2.6Hz), 10.52(1H, s) 12

¹H—NMR(DMSO-d₆)δ3.99(2H, q, J=5.3Hz), 7.14(1H, d, J=7.6Hz), 7.14( 1H, d, J=8.9Hz), 7.36(1H, dd, J=7.6, 7.6Hz), 7.53(1H, d, J=7.6Hz), 7.67(1H, d, J=8.9Hz), 7.73(1H, s), 8.10(1H, s), 8.49(3H, brs), 9.87( 1H, brs)

TABLE 45 Example Reagent Product Spectral data 14

¹H—NMR(DMSO-d₆)δ2.36(3H, s), 3.97(2H, q, J=5.6Hz), 6.91(1H, d, J= 5.0Hz), 7.19(1H, d, J=7.6Hz), 7.34(1H, dd, J=7.6, 7.6Hz), 7.55(1H, d, J= 7.6Hz), 7.64(1H, s), 8.20(1H, d, J=5.0Hz), 8.48(3H, brs), 9.08(1H, s) 16

¹H—NMR(DMSO-d₆)δ2.26(3H, s), 3.56(3H, brs), 4.03(2H, q, J=5.6Hz), 6.96(1H, d, J=5.9Hz), 7.30-7.38(3H, m), 7.48(1H, dd, J=7.9, 7.9Hz), 7.53(1H, s), 8.58(3H, brs), 10.23(1H, brs) 18

¹H—NMR(DMSO-d₆)δ3.92(3H, s), 4.03(2H, s), 6.41(1H, d, J=9.2Hz), 7.31(1H, d, J=7.9Hz), 7.45(1H, dd, J=7.9, 7.9Hz), 7.77-7.87(2H, m), 8.46(1H, d, J=9.2Hz), 8.48(3H, brs), 10.49(1H, brs) 20

¹H—NMR(DMSO-d₆)δ3.83(3H, s), 3.98(2H, s), 6.33(1H, d, J=8.6Hz), 7.09 (1H, d, J=7.3Hz), 7.36(1H, dd, J=7.3, 7.3Hz), 7.61(1H, d, J=7.3Hz), 7.63 (1H, d, J=8.6Hz), 7.76(1H, s)

TABLE 46 Example Reagent Product Spectral data 22

¹H—NMR(DMSO-d₆)δ3.86(3H, s), 3.89(3H, s), 3.98(2H, s), 6.36(1H, d, J=8.9Hz), 7.12(1H, d, J=8.9Hz), 7.71(1H, s), 7.77(1H, d, J=8.9Hz), 8.31(3H, brs), 8.43(1H, d, J=8.9Hz), 10.42(1H, s) 24

¹H—NMR(DMSO-d₆)δ1.19(3H, t, J=7.6Hz), 2.70(2H, q, J=7.6Hz), 3.94( 3H, s), 4.04(2H, s), 6.40(1H, d, J=9.2Hz), 7.31(1H, s, J=8.6Hz), 7.71( 1H, d, J=1.3Hz), 7.84(1H, dd, J=8.6, 1.3Hz), 8.40(3H, brs), 8.46(1H, d, J=9.2Hz), 10.50(1H, s) 26

¹H—NMR(DMSO-d₆)δ1.22(3H, t, J=7.3Hz), 2.59(2H, q, J=7.3Hz), 3.63( 4H, s), 3.94(3H, s), 6.42(1H, d, J=9.2Hz), 7.29-7.44(5H, m), 7.52(1H, s), 8.05(1H, d, J=8.6Hz), 8.47(1H, d, J=9.2Hz), 8.68(3H, bs), 10.55 (1H, s) 28

¹H—NMR(DMSO-d₆)δ4.03(2H, s), 7.05(1H, d, J=8.6Hz), 7.35(1H, d, J= 7.6Hz), 7.47(1H, dd, J=7.6, 7.6Hz), 7.62(1H, s), 7.73(1H, d, J=7.6Hz ), 8.48(3H, brs), 8.57(1H, d, J=8.6Hz), 10.15(1H, s)

TABLE 47 Example Reagent Product Spectral data 30

¹H—NMR(DMSO-d₆)δ2.93(3H, s), 4.04(2H, s), 6.19(1H, d, J=9.2Hz), 7.24(1H, d, J=7.6Hz), 7.44(1H, dd, J=7.6, 7.6Hz), 7.80(1H, s), 7.98( 1H, d, J=7.6Hz), 8.10(1H, d, J=9.2Hz) 32

¹H—NMR(DMSO-d₆)δ1.17(3H, t, J=7.3Hz), 3.40(2H, q, J=7.3Hz), 4.01( 2H, q, J=5.3Hz), 6.06(1H, brs), 6.19(1H, d, J=9.2Hz), 7.26(1H, d, J= 7.3Hz), 7.42(1H, dd, J=7.3, 7.3Hz), 7.77(1H, s), 7.93(1H, d, J=7.3Hz ), 8.09(1H, d, J=9.2Hz), 8.52(3H, brs), 10.98(1H, s) 34

¹H—NMR(DMSO-d₆)δ0.92(3H, t, J=7.3Hz), 1.55-1.63(2H, m), 3.29-3.40 (2H, m), 4.01(2H, q, J=5.3Hz), 6.10(1H, brs), 6.21(1H, d, J=9.2Hz), 7.27(1H, d, J=7.6Hz), 7.41(1H, dd, J=7.6, 7.6Hz), 7.73(1H, s), 7.97( 1H, d, J=7.6Hz), 8.09(1H, d, J=9.2Hz), 8.53(3H, brs), 10.98(1H, s) 36

¹H—NMR(DMSO-d₆)δ3.19(6H, s), 4.01(2H, s), 6.40(1H, d, J=9.6Hz), 7.26(1H, d, J=7.6Hz), 7.42(1H, dd, J=7.6, 7.6Hz), 7.75(1H, s), 7.88( 1H, d, J=7.6Hz), 8.21(1H, d, J=9.6Hz), 8.46(3H, brs), 10.78(1H, s)

TABLE 48 Example Reagent Product Spectral data 38

¹H—NMR(DMSO-d₆)δ4.01(2H, s), 6.93(1H, d, J=8.1Hz), 7.21(1H, d, J= 7.6Hz), 7.42(1H, dd, J=7.6, 7.6Hz), 7.55(1H, s), 7.93(1H, d, J=7.6Hz ), 8.25(1H, d, J=8.1Hz), 8.46(3H, brs), 10.66(1H, s) 40

¹H—NMR(DMSO-d₆)δ3.88(3H, s), 3.94(2H, q, J=5.6Hz), 6.16(1H, d, J= 7.9Hz), 6.49(1H, d, J=7.9Hz), 6.62(2H, brs), 7.05(1H, d, J=7.6Hz), 7.30(1H, dd, J=7.6, 7.6Hz), 7.49(1H, dd, J=7.9, 7.9Hz), 7.63(1H, d, J= 7.6Hz), 7.80(1H, s), 8.50(3H, brs) 42

¹H—NMR(DMSO-d₆)δ3.41(2H, s), 6.39(1H, dd, J=7.3, 5.9Hz), 6.68—6.89 (4H, m), 7.35(1H, d, J=5.9Hz), 7.67(1H, d, J=7.3Hz) 44

¹H—NMR(DMSO-d₆)δ3.87(3H, s), 3.95(3H, s), 4.01(2H, brs), 6.29(1H, d, J=8.6Hz), 7.15(1H, d, J=7.6Hz), 7.40(1H, dd, J=7.9, 7.6Hz), 7.74( 1H, s), 7.88(1H, d, J=7.9Hz), 8.16(1H, d, J=8.6Hz), 8.30(3H, brs), 10.47(1H, s)

TABLE 49 Example Reagent Product Spectral data 57

¹H—NMR(DMSO-d₆)δ1.32(3H, t, J=7.3Hz), 4.03(2H, s), 4.36(2H, q, J= 7.3Hz), 6.39(1H, d, J=8.9Hz), 7.31(1H, d, J=7.6Hz), 7.45(1H, dd, J= 7.6, 7.6Hz), 7.75(1H, s), 7.79(1H, d, J=7.6Hz), 8.45(1H, d, J=8.9Hz), 8.45(3H, brs), 10.49(1H, s) 61

¹H—NMR(DMSO-d₆)δ3.33(3H, s), 4.03(2H, s), 6.91(1H, d, J=8.9Hz), 7.31(1H, d, J=7.6Hz), 7.45(1H, dd, J=7.6, 7.6Hz), 7.72-7.29(2H, m), 8.34(1H, d, J=8.9Hz), 8.44(3H, brs), 10.33(1H, s) 77

¹H—NMR(DMSO-d₆)δ10.50(1H, brs), 8.45(1H, d, J=9.2Hz), 8.30(3H, brs), 7.78(1H, dd, J=8.3, 2.0Hz), 7.67(1H, d, J=2.0Hz), 7.28(1H, d, J= 8.3Hz), 6.38(1H, d, J=9.2Hz), 4.03(2H, s), 3.93(3H, s), 2.37(3H, s) 108

¹H—NMR(DMSO-d₆)δ3.99(3H, s), 4.04(2H, q, J=5.6Hz), 6.40(1H, d, J= 8.6Hz), 7.19(1H, d, J=7.9Hz), 7.43(1H, dd, J=7.9, 7.9Hz), 7.74(1H, s ), 7.97(1H, d, J=7.9Hz), 8.09(1H, d, J=8.6Hz), 8.27(3H, brs), 9.78( 1H, s), 10.96(1H, s)

TABLE 50 Example Reagent Product Spectral data 151

¹H—NMR(DMSO-d₆)δ2.28(3H, s), 4.03(2H, s), 6.75(1H, d, J=8.9Hz), 7.08(1H, s), 7.27-7.36(2H, m), 7.42-7.49(2H, m), 8.04(1H, d, J=8.9 Hz), 8.30(3H, brs), 9.40(1H, s) 153

¹H—NMR(DMSO-d₆)δ3.77(3H, s), 4.05(2H, q, J=4.6Hz), 6.53(1H, dd, J= 9.2, 2.3Hz), 6.60(1H, d, J=2.3Hz), 7.34(1H, d, J=7.6Hz), 7.39(1H, d, J=7.6Hz), 7.48(1H, dd, J=7.6, 7.6Hz), 7.54(1H, s), 8.15(1H, d, J=9.2 Hz), 8.46(3H, brs), 9.65(1H, s) 457

¹H—NMR(DMSO-d₆)δ10.43(1H, brs), 8.40(3H, brs), 8.28(1H, d, J=8.9 Hz), 7.87(1H, s), 7.62-7.54(1H, m), 7.41(1H, dd, J=7.9, 7.6Hz), 7.22 (1H, d, J=7.6Hz), 6.61(1H, d, J=8.9Hz), 4.06(3H, s), 4.01(2H, brs) FAB—MX(m/z) 275(M* + 1) 458

¹H—NMR(DMSO-d₆)δ10.34(1H, brs), 8.43(1H, d, J=8.9Hz), 8.42-8.20 (4H, m), 7.77(1H, dd, J=5.0, 4.6Hz), 7.32(1H, d, J=4.6Hz), 6.33(1H, d, J=8.9Hz), 4.11(2H, s), 3.72(3H, s), 2.29(3H, s) FAB—MS(m/z) 289(M* + 1)

TABLE 51 Example Reagent Product Spectral data 459

¹H—NMR(DMSO-d₆)δ10.52(1H, brs), 8.45(1H, d, J=9.2Hz), 8.45-8.28( 4H, m), 8.02-7.73(2H, m), 7.40(1H, brs), 6.40(1H, d, J=9.2Hz), 4.23( 2H, s), 3.94(3H, s), 3.50-3.20(4H, m), 2.21-1.95(4H, m) FAB—MS(m/z) 344(M* + 1) 460

¹H—NMR(DMSO-d₆)δ10.50(1H, s), 8.44(1H, d, J=8.9Hz), 7.98(3H, brs), 7.69(2H, d, J=7.9Hz), 7.28(2H, d, J=7.9Hz), 6.26(1H, d, J=8.9Hz), 3.92(3H, s), 3.15-2.97(2H, m), 2.93(2H, t, J=7.6Hz) FAB—MS(m/z) 289(M* + 1) 461

¹H—NMR(DMSO-d₆)δ11.06(1H, s), 8.63(1H, s), 8.46(1H, d, J=8.9Hz), 8.33(3H, brs), 7.57(1H, d, J=7.3Hz), 7.15-7.10(1H, m), 6.38(1H, d, J=8.9Hz), 4.08(2H, s), 3.98(6H, s) FAB—MS(m/z) 305(M* + 1) 462

¹H—NMR(DMSO-d₆)δ10.52(1H, s), 8.57(3H, brs), 8.46(1H, d, J=9.2Hz), 7.84(1H, d, J=7.9Hz), 7.75(1H, s), 7.47(1H, dd, J=8.2, 7.9Hz), 7.42- 7.35(1H, m), 6.41-6.37(1H, m), 3.91(3H, s), 1.67(6H, s) FAB—MS(m/z) 303(M* + 1)

TABLE 52 Example Reagent Product Spectral data 463

¹H—NMR(DMSO-d₆)δ10.49(1H, s), 8.45(1H, d, J=8.9Hz), 8.35(3H, brs), 7.68(1H, s), 7.61(1H, s), 7.12(1H, s), 6.40(1H, d, J=8.9Hz), 3.99(2H, s), 3.95(3H, s), 2.36(3H, s) FAB—MS(m/z) 289(M* + 1) 464

¹H—NMR(DMSO-d₆)δ10.20(1H, brs), 8.43(1H, d, J=9.2Hz), 7.95(3H, brs), 7.50(1H, dd, J=7.9, 1.7Hz), 7.40-7.25(3H, m), 6.30(1H, d, J=9.2 Hz), 3.58(3H, s), 3.03-2.88(4H, m) FAB—MS(m/z) 289(M* + 1) 465

¹H—NMR(DMSO-d₆)δ11.09(1H, s), 8.58-8.53(1H, m), 8.51(1H, d, J=9.2 Hz), 8.40(3H, brs), 7.32-7.28(2H, m), 6.46(1H, d, J=9.2Hz), 4.11(2H, s), 4.01(3H, s), 3.84(3H, s) FAB—MS(m/z) 305(M* + 1) 466

¹H—NMR(DMSO-d₆)δ10.51(1H, brs), 8.50(3H, brs), 8.47(1H, d, J=9.2Hz ), 7.93-7.89(2H, m), 7.55(1H, d, J=9.2Hz), 6.43(1H, d, J=9.2Hz), 4.14 (2H, s), 3.93(3H, s) FAB—M(m/z) 309(M* + 1)

TABLE 53 Example Reagent Product Spectral data 467

¹H—NMR(DMSO-d₆)δ10.45(1H, brs), 8.58-8.37(4H, m), 7.87-7.79(2H, m ), 7.31(1H, dd, J=9.2, 8.9Hz), 6.39(1H, d, J=8.9Hz), 4.07(2H, s), 3.89 (3H, s) 468

¹H—NMR(DMSO-d₆)δ11.10(1H, s), 8.57-8.53(1H, m), 8.50(1H, d, J=9.2 Hz), 8.37(3H, brs), 7.35-7.24(2H, m), 6.46(1H, d, J=9.2Hz), 4.10(2H, s), 4.01(3H, s), 3.96(2H, q, J=6.9Hz), 1.45(3H, t, J=6.9Hz) 469

¹H—NMR(DMSO-d₆)δ10.85(1H, brs), 8.50(1H, d, J=9.2Hz), 8.49(3H, brs), 8.39(1H, d, J=7.9Hz), 7.51(1H, dd, J=7.9, 7.6Hz), 7.42(1H, d, J= 7.6Hz), 6.47(1H, d, J=9.2Hz), 4.22(2H, s), 3.90(3H, s) 470

¹H—NMR(DMSO-d₆)δ9.52(1H, s), 8.35(3H, brs), 7.79(1H, s), 7.70-7.64 (1H, m), 7.35-7.27(1H, m), 7.06(1H, d, J=7.6Hz), 6.98(1H, s), 6.87 (1H, s), 4.02(2H, s), 3.93(3H, s), 3.87(3H, s)

TABLE 54 Example Reagent Product Spectral data 471

¹H—NMR(DMSO-d₆)δ13.28(1H, brs), 9.47(1H, s), 8.34(3H, brs), 7.79 (1H, s), 7.65(1H, d, J=8.6Hz), 7.33(1H, dd, J=8.6, 7.3Hz), 7.06(1H, d, J=7.3Hz), 6.96(1H, s), 6.53(1H, s), 3.97(2H, d, J=5.3Hz), 3.92(3H, s) 473

¹H—NMR(D₂O)δ7.63-7.52(1H, m), 7.45-7.37(3H, m), 6.54(1H, s), 6.41 (1H, s), 4.22(2H, s), 4.02(3H, s), 2.37(3H, s) 474

¹H—NMR(DMSO-d₆)δ9.89(1H, brs), 8.43(3H, brs), 8.38(1H, d, J=5.3Hz ), 7.83(1H, s), 7.73(1H, d, J=7.9Hz), 7.34(1H, dd, J=7.9, 7.6Hz), 7.13 (1H, d, J=7.6Hz), 6.82(1H, d, J=5.3Hz), 3.97(2H, q, J=5.6Hz), 2.41( 3H, s)

TABLE 55 Example Reagent Product Spectral data 475

¹H—NMR(DMSO-d₆)δ3.78(3H, s), 3.98(2H, s), 6.33(1H, d, J=8.2Hz), 7.18(1H, d, J=7.6Hz), 7.35(1H, dd, J=7.6, 7.6Hz), 7.57(1H, d, J=7.6Hz ), 7.69(1H, s), 7.84(1H, d, J=8.2Hz), 8.16(1H, s), 8.37(3H, brs) 476

¹H—NMR(DMSO-d₆)δ3.81(3H, s), 3.98(2H, s), 7.17(1H, d, J=7.6Hz), 7.21(1H, d, J=7.6Hz), 7.25(1H, dd, J=9.2, 3.0Hz), 7.32(1H, s), 7.38 (1H, dd, J=7.6, 7.6Hz), 7.39(1H, d, J=9.2Hz), 7.57(1H, d, J=3.0Hz), 8.36(3H, brs), 9.02(1H, s) 477

¹H—NMR(DMSO-d₆)δ2.18(3H, s), 3.87(2H, s), 6.58(1H, d, J=7.9Hz), 6.63(1H, s), 6.87(1H, d, J=7.6Hz), 7.18(1H, dd, J=7.6, 7.6Hz), 7.32 (1H, dd, J=7.9, 7.9Hz), 7.62(1H, d, J=7.6Hz), 7.80(1H, d, J=7.9Hz), 8.12(1H, s), 8.28(3H, brs) 478

¹H—NMR(DMSO-d₆)δ2.40(3H, s), 4.05(2H, q, J=5.3Hz), 6.93(1H, d, J= 6.3Hz), 7.14(1H, s), 7.34-7.39(2H, m), 7.49(1H, dd, J=7.6, 7.6Hz), 7.62(1H, s), 8.02(1H, d, J=6.3Hz), 8.59(3H, brs), 10.83(1H, brs)

TABLE 56 Example Reagent Product Spectral data 479

¹H—NMR(DMSO-d₆)δ1.66(6H, s), 2.38(3H, s), 6.90(1H, d, J=6.3Hz), 7.04(1H, s), 7.40-7.53(3H, m), 7.62(1H, s), 8.00(1H, d, J=6.3Hz), 8.76(3H, brs), 10.52(1H, brs) 480

¹H—NMR(DMSO-d₆)δ0.81(3H, t, J=7.3Hz), 1.83-2.06(2H, m), 2.39(3H, s), 4.10-4.25(1H, m), 6.92(1H, d, J=6.3Hz), 7.11(1H, s), 7.37(1H, d, J=7.6Hz), 7.39(1H, d, J=7.6Hz), 7.50(1H, dd, J=7.6, 7.6Hz), 7.60(1H, s), 8.02(1H, d, J=6.3Hz), 8.69(3H, brs), 10.76(1H, brs) 481

¹H—NMR(DMSO-d₆)δ2.26(3H, s), 2.38(3H, s), 4.11(2H, q, J=5.3Hz), 6.87(1H, d, J=6.9Hz), 6.87(1H, s), 7.33-7.52(3H, m), 7.92(1H, d, J= 6.9Hz), 8.58(3H, brs), 10.67(1H, brs) 482

¹H—NMR(DMSO-d₆)δ1.20(3H, t, J=7.6Hz), 2.41(3H, s), 2.72(2H, q, J= 7.6Hz), 4.07(2H, q, J=5.6Hz), 6.92(1H, d, J=6.3Hz), 7.12(1H, s), 7.30 (1H, d, J=8.3Hz), 7.35(1H, d, J=8.3Hz), 7.57(1H, s), 8.00(1H, d, J=6.3 Hz), 8.61(3H, brs), 10.79(1H, brs)

TABLE 57 Example Reagent Product Spectral data 483

¹H—NMR(DMSO-d₆)δ1.40(3H, t, J=6.9Hz), 2.38(3H, s), 3.99(2H, q, J= 5.3Hz), 4.13(2H, q, J=6.9Hz), 6.87(1H, d, J=6.3Hz), 7.03(1H, s), 7.15 (1H, d, J=8.9Hz), 7.33(1H, dd, J=8.9, 1.7Hz), 7.51(1H, d, J=1.7Hz), 7.94(1H, d, J=6.3Hz), 8.48(3H, brs), 10.72(1H, brs) 484

¹H—NMR(DMSO-d₆)δ2.37(3H, s), 2.88-3.10(4H, m), 6.88(1H, d, J=6.6 Hz), 6.95(1H, s), 7.39-7.50(4H, m), 7.89(1H, d, J=6.6Hz), 8.12(3H, brs), 10.69(1H, brs) 485

¹H—NMR(DMSO-d₆)δ2.39(3H, s), 4.19(2H, q, J=5.0Hz), 6.93(1H, d, J= 6.3Hz), 6.98(1H, s), 7.48-7.68(3H, m), 7.97(1H, d, J=6.3Hz), 8.71( 3H, brs), 10.56(1H, brs) 486

¹H—NMR(DMSO-d₆)δ2.35(3H, s), 2.49(3H, s), 4.05(2H, q, J=5.3Hz), 6.82(1H, s), 7.00(1H, s), 7.33-7.38(2H, m), 7.48(1H, dd, J=7.6, 7.6Hz ), 7.56(1H, s), 8.58(3H, brs), 10.30(1H, brs)

TABLE 58 Example Reagent Product Spectral data 487

¹H—NMR(DMSO-d₆)δ1.20(3H, t, J=7.3Hz), 2.71(2H, q, J=7.3Hz), 4.05 (2H, q, J=5.3Hz), 6.98(1H, d, J=6.3Hz), 7.18(1H, s), 7.34-7.42(2H, m ), 7.49(1H, dd, J=7.6, 7.6Hz), 7.64(1H, s), 8.03(1H, d, J=6.3Hz), 8.66 (3H, brs), 11.00(1H, brs) 488

¹H—NMR(DMSO-d₆)δ1.73-1.85(1H, m), 2.15-2.27(1H, m), 2.40(3H, s), 2.56-2.66(4H, m), 6.92(1H, d, J=6.3Hz), 7.13(1H, s), 7.35-7.42(2H, m ), 7.53(1H, dd, J=7.6, 7.6Hz), 7.63(1H, s), 8.00(1H, d, J=6.3Hz), 8.94 (3H, brs), 10.84(1H, brs) 489

¹H—NMR(DMSO-d₆)δ2.37(3H, s), 2.87-3.15(4H, m), 6.87(1H, d, J=6.3 Hz), 7.01(1H, s), 7.37(4H, s), 7.92(1H, d, J=6.3Hz), 8.16(3H, brs), 10.65(1H, brs) 490

¹H—NMR(DMSO-d₆)δ1.13(3H, t, J=6.9Hz), 2.40(3H, s), 3.86(2H, q, J= 6.9Hz), 4.06(2H, q, J=5.3Hz), 6.93(1H, d, J=5.9Hz), 7.07(1H, s), 7.28 (1H, dd, J=7.6, 7.6Hz), 7.45(1H, d, J=7.6Hz), 7.51(1H, d, J=7.6Hz), 7.96(1H, d, J=5.9Hz), 8.54(3H, brs), 10.71(1H, brs)

TABLE 59 Example Reagent Product Spectral data 491

¹H—NMR(DMSO-d₆)δ2.41(3H, s), 4.14(2H, q, J=5.3Hz), 6.95(1H, d, J= 6.3Hz), 7.18(1H, s), 7.44(1H, dd, J=8.6, 2.0Hz), 7.58(1H, d, J=8.6Hz ), 7.79(1H, d, J=2.0Hz), 8.04(1H, d, J=6.3Hz), 8.76(3H, brs), 10.89( 1H, brs) 492

¹H—NMR(DMSO-d₆)δ3.86(3H, s), 4.01(2H, q, J=5.9Hz), 6.36(1H, d, J= 8.5Hz), 7.19(1H, d, J=7.8Hz), 7.38(1H, dd, J=7.8, 7.8Hz), 7.63(1H, d, J=7.8Hz), 7.77(1H, s), 7.95(1H, d, J=8.5Hz), 8.41(3H, brs), 9.28(1H, s) 493

¹H—NMR(DMSO-d₆)δ3.98(2H, q, J=5.3Hz), 6.86(1H, d, J=7.9, 5.0Hz), 7.14(1H, d, J=7.6Hz), 7.34(1H, dd, J=7.6, 7.6Hz), 7.66(1H, d, J=7.6Hz ), 7.76-7.86(2H, m), 8.10(1H, dd, J=5.0, 1.3Hz), 8.38(3H, brs), 8.47 (1H, s) 494

¹H—NMR(DMSO-d₆)δ3.93(3H, s), 4.01(2H, q, J=5.9Hz), 6.24(1H, d, J= 8.6Hz), 7.08(1H, d, J=7.9Hz), 7.37(1H, dd, J=7.9, 7.9Hz), 7.42(1H, brs), 7.65(1H, s), 7.88(1H, d, J=7.9Hz), 8.04(1H, brs), 8.14(1H, d, J= 8.6Hz), 8.22(3H, brs), 11.76(1H, s)

TABLE 60 Example Reagent Product Spectral data 495

¹H—NMR(DMSO-d₆)δ2.19(3H, s), 3.79(3H, s), 3.94(2H, q, J=5.6Hz), 6.16(1H, d, J=7.6Hz), 7.03(1H, d, J=7.9Hz), 7.29(1H, dd, J=7.9, 7.9Hz ), 7.36(1H, d, J=7.6Hz), 7.64(1H, d, J=7.9Hz), 7.82(1H, s), 7.95(1H, brs), 8.35(3H, brs) 496

¹H—NMR(DMSO-d₆)δ3.74(3H, s), 3.88(3H, s), 4.00(2H, q, J=5.3Hz), 6.35(1H, d, J=2.3Hz), 6.46(1H, dd, J=9.6, 2.3Hz), 7.15(1H, d, J=8.6Hz ), 7.40(1H, d, J=8.6Hz), 7.43(1H, s), 8.13(1H, d, J=9.6Hz), 8.18(3H, brs), 9.60(1H, s) 501

¹H—NMR(DMSO-d₆)δ2.25(3H, s), 4.21(2H, q, J=5.6Hz), 7.26-7.50(4H, m), 7.62(1H, s), 7.88(1H, d, J=10.2Hz), 7.95(1H, s), 8.57(3H, brs), 10.77(1H, brs) 502

¹H—NMR(DMSO-d₆)δ2.40(3H, s), 4.04(2H, q, J=5.6Hz), 7.42(1H, dd, J= 6.6, 6.6Hz), 7.40-7.57(3H, m), 7.66(1H, s), 7.90-7.99(2H, m), 8.65( 3H, brs), 9.77(1H, brs)

TABLE 61 Example Reagent Product Spectral data 503

¹H-NMR(CDCl₃)δ2.38(3H, s), 3.88(3H, s), 3.99(2H, q, J=5.6Hz), 6.87 (1H, d, J=6.3Hz), 7.02(1H, s), 7.17(1H, d, J=8.6Hz), 7.36(1H, dd, J= 8.6, 2.0Hz), 7.51(1H, d, J=2.0Hz), 7.94(1H, d, J=6.3Hz), 8.46(3H, brs), 10.70(1H, brs) 504

¹H-NMR(CDCl₃)δ2.43(3H, s), 3.99(2H, q, J=5.3Hz), 6.61(1H, s), 6.97( 1H, d, J=5.9Hz), 7.23(1H, s), 7.53-7.64(2H, m), 7.83(1H, s), 7.88(1H, s), 8.07(1H, d, J=5.9Hz), 8.24-8.28(1H, m), 8.66(3H, brs), 11.01(1H, brs) 506

¹H-NMR(DMSO-d6)δ8.46(3H, brs), 7.95(1H, d, J=6.3Hz), 7.55-7.36( 2H, m), 7.28(1H, dd, J=7.9, 7.6Hz), 7.01(1H, s), 6.91(1H, d, J=6.3Hz), 4.06(2H, q, J=5.3Hz), 3.75(2H, t, J=6.6Hz), 2.40(3H, s), 1.60-1.51 (2H, m), 0.76(3H, t, J=7.3Hz) 521

¹H-NMR(DMSO-d6)δ1.13(3H, t, J=6.9Hz), 2.42(3H, s), 3.91(2H, q, J= 6.9Hz), 4.16(2H, q, J=5.0Hz), 6.95(1H, d, J=6.3Hz), 7.13(1H, s), 7.42 (1H, d, J=8.6Hz), 7.51(1H, d, J=8.6Hz), 7.95(1H, d, J=6.3Hz), 8.54 (3H, brs), 10.96(1H, brs)

TABLE 62 Example Reagent Product Spectral data 522

¹H-NMR(DMSO-d₆)δ1.10(3H, t, J=6.9Hz), 2.41(3H, s), 2.46(3H, s), 3.84(2H, q, J=6.9Hz), 3.96-4.19(2H, m), 6.91(1H, d, J=6.3Hz), 7.04- 7.19(2H, m), 7.30(1H, d, J=7.9Hz), 7.94(1H, d, J=6.3Hz), 8.47(3H, brs), 10.95(1H, brs) 541

¹H-NMR(DMSO-d₆)δ10.68(1H, brs), 8.46(3H, brs), 7.94(1H, d, J=5.9 Hz), 7.55-7.36(2H, m), 7.32-7.22(1H, m), 7.06(1H, s), 6.90(1H, d, J= 5.9Hz), 4.06(2H, s), 3.67(3H, s), 2.40(3H, s) 543

¹H-NMR(DMSO-d₆)δ10.66(1H, brs), 8.48(3H, brs), 7.95(1H, d, J=6.3Hz ), 7.50(1H, d, J=8.3Hz), 7.44(1H, d, J=7.6Hz), 7.27(1H, dd, J=8.3, 7.6 Hz), 7.06(1H, s), 6.92(1H, d, J=6.3Hz), 4.27-4.12(1H, m), 4.07(2H, q, J=5.3Hz), 2.41(3H, s), 1.07(6H, d, J=5.9Hz)

Example 3 Synthesis of 3-amino-2-(3-(di(t-butoxycarbonyl)aminomethyl)phenyl-amino)pyridine

A mixture of the compound (1.41 g) obtained in Example 1, 10% palladium-carbon (170 mg), methanol (60 ml) and ethyl acetate (30 ml) was stirred in a hydrogen atmosphere at room temperature for one day. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 1.15 g of the titled compound (yield, 88%).

¹H-NMR (CDCl₃) δ: 1.45(18H, s), 3.40(2H, brs), 4.75(2H, s), 6.20(1H, brs), 6.77(1H, dd, J=7.6, 5.0 Hz), 6.84-6.90(1H, m), 7.00(1H, dd, J=7.6, 1.3 Hz), 7.13(1H, s), 7.19-7.23(2H, m), 7.82 (1H, dd, J=5.0, 1.3 Hz)

The procedure of Example 3 was repeated using corresponding reagents to give the compounds shown in Table 63.

TABLE 63 Example Reagent Product Spectral data 11

¹H-NMR(CDCl₃)δ1.45(18H, s), 3.38(2H, brs), 4.74(2H, s), 6.35(1H, brs ), 6.83(1H, d, J=8.9Hz), 6.86(1H, d, J=7.6Hz), 6.98(1H, dd, J=8.9, 2.6Hz ), 7.10(1H, s), 7.12(1H, d, J=7.6Hz), 7.20(1H, dd, J=7.6, 7.6Hz), 7.79( 1H, d, J=2.6Hz) 15

¹H-NMR(CDCl₃)δ1.44(18H, s), 2.22(3H, s), 3.41(2H, brs), 4.73(2H, s), 6.11(1H, brs), 6.72(1H, d, J=5.0Hz), 6.85(1H, d, J=7.6Hz), 7.01(1H, s), 7.07(1H, d, J=7.6Hz), 7.20(1H, dd, J=7.6, 7.6Hz), 7.72(1H, d, J=5.0Hz) 19

¹H-NMR(CDCl₃)δ1.44(18H, s), 3.88(3H, s), 4.76(2H, s), 6.15(1H, d, J= 8.3Hz), 6.74(1H, brs), 6.86(1H, d, J=7.8Hz), 7.06(1H, d, J=8.3Hz), 7.23 (1H, dd, J=7.8, 7.8Hz), 7.36(1H, s), 7.49(1H, d, J=7.8Hz) 445

¹H-NMR(CDCl₃)δ7.35(1H, s), 7.30-7.23(2H, m), 6.92-6.87(1H, m), 6.31 (1H, brs), 6.12(1H, s), 6.05(1H, s), 4.81(1H, brs), 4.30(2H, d, J=5.6Hz), 3.89(3H, s), 2.22(3H, s), 1.46(9H, s) 455

¹H-NMR(CDCl₃)δ1.46(9H, s), 2.17(3H, s), 3.91(3H, s), 4.31(2H, d, J= 5.6Hz), 4.80(1H, brt), 6.13(1H, s), 6.18(1H, d, J=7.9Hz), 6.89(1H, d, J= 7.3Hz), 7.21-7.30(2H, m), 7.49(1H, d, J=7.3Hz), 7.62(1H, s)

Example 5 Synthesis of 3-methylamino-2-(3-(di-(t-butoxycarbonyl)aminomethyl)phenylamino)pyridine

To a mixture of the compound (88.5 mg) obtained in Example 3, methyl iodide (15 μl) and dimethylformamide (2 ml), sodium hydride (content=60%; 10 mg) was added and the resulting mixture was stirred at room temperature for 4 days. To the reaction mixture, ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:3) to give 19.3 mg of the titled compound (yield, 21%).

¹H-NMR (CDCl₃) δ: 1.44(18H, s), 2.85(3H, s), 3.48(1H, brs), 4.74(2H, s), 6.02(1H, s), 6.82-6.95(3H, m), 7.03(1H, s), 7.09(1H, d, J=8.0 Hz), 7.20(1H, dd, J=8.0, 8.0 Hz), 7.75 (1H, dd, J=4.3, 1.7 Hz)

Example 6 Synthesis of 3-methylamino-2-(3-aminomethylphenylamino)pyridine

Using the compound obtained in Example 5 as a starting material, reaction was performed as in Example 2 and thereafter the liquid reaction mixture was concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (eluent, chloroform: methanol=10:1) to give the titled compound quantitatively.

¹H-NMR (CDCl₃) δ: 1.69(2H, brs), 2.85(3H, s), 3.53(1H, brs), 3.81(2H, s), 6.08(1H, brs), 6.84-6.94(3H, m), 7.05(1H, d, J=7.6 Hz), 7.12(1H, s), 7.22(1H, dd, J=7.6, 7.6 Hz), 7.76 (1H, dd, J=4.6, 2.0 Hz)

Example 7 Synthesis of 3-ethylamino-2-(3-(di-(t-butoxycarbonyl)aminomethyl)phenylamino)pyridine

Using the compound obtained in Example 3 as a starting material and also using ethyl iodide as a reagent, the procedure of Example 5 was repeated to give the titled compound (yield, 54%).

¹H-NMR (CDCl₃)

δ: 1.28(3H, t, J=7.3 Hz), 1.45(18H, s), 3.15(2H, q, J=7.3 Hz), 3.30(1H, brs), 4.74(2H, s), 6.05(1H, s), 6.82-6.96(3H, m), 7.07(1H, s), 7.12-7.18(1H, m), 7.18 (1H, dd, J=7.3, 7.3 Hz), 7.75(1H, dd, J=4.6, 1.3 Hz)

Example 29 Synthesis of 2-(3-(di-(t-butoxycarbonyl)aminomethyl)phenylamino)-6-methylamino-3-nitropyridine

A mixture of the compound (77.0 mg) obtained in Example 27, potassium carbonate (89 mg), methylamine hydrochloride (22.0 mg) and acetonitrile (2 ml) was stirred at 60° C. for 6 h and the reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the resulting residue. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 71.0 mg of the titled compound (yield, 93%).

¹H-NMR (CDCl₃) δ: 1.43(18H, s), 3.03(3H, d, J=4.3 Hz), 4.81(2H, s), 5.93(1H, d, J=8.9 Hz), 6.98-7.80(5H, m), 8.20-8.42(1H, m), 10.81(1H, brs)

The procedure of Example 29 was repeated using corresponding amine derivatives to give the compounds shown in Table 64.

TABLE 64 Amine Example derivative Product Spectral data 31 NH₂EtHCl

¹H-NMR(CDCl₃)δ1.32(3H, t, J=6.9Hz), 1.43( 18H, s), 3.38-3.52(2H, m), 4.81(2H, s), 5.92( 1H, d, J=9.2Hz), 6.97-7.78(5H, m), 8.26(1H, d, J=9.2Hz), 10.79(1H, brs) 33 NH₂ ^(a)Pr.HCl

¹H-NMR(CDCl₃)δ1.00(3H, t, J=7.3Hz), 1.43( 18H, s), 1.62-1.80(2H, m), 3.22-3.44(2H, m), 4.81(2H, s), 5.92(1H, d, J=6.5Hz), 6.95-7.83( 5H, m), 8.20-8.37(1H, m), 10.80(1H, brs) 35 NHMe₂.HCl

¹H-NMR(CDCl₃)δ1.46(18H, s), 3.19(6H, s), 4.78(2H, s), 6.08(1H, d, J=9.6Hz), 7.04(1H, d, J=7.6Hz), 7.29(1H, dd, J=7.6, 7.6Hz), 7.58( 1H, s), 7.59(1H, d, J=7.6Hz), 8.28(1H, d, J=9.6 Hz), 10.81(1H, brs)

Example 37 Synthesis of 6-chloro-2-(3-(t-butoxycarbonylaminomethyl)phenylamino)nicotinic acid

A mixture of 3-(di-(t-butoxycarbonyl)aminomethyl)aniline (81 mg), 2,6-dichloronicotinic acid (90%, 53 mg), di-i-propylethylamine (64 mg) and 1,4-dioxane (1 ml) was heated under reflux for 3 days and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, methylene chloride:methanol=20:1) to give 24 mg of the titled compound (yield, 25%).

¹H-NMR (DMSO-d₆) δ: 1.44(9H, s), 4.14-4.26(2H, m), 6.72(1H, d, J=7.9 Hz), 6.89(1H, d, J=7.6 Hz), 7.09(1H, brt), 7.26(1H, dd, J=7.6, 7.6 Hz), 7.51(1H, s), 7.71 (1H, d, J=7.6 Hz), 8.22(1H, d, J=7.9 Hz)

Example 39 Synthesis of 2-(3-(di-(t-butoxycarbonyl)aminomethyl)phenylamino)-6-methoxypyridine

A mixture of 3-(di-(t-butoxycarbonyl)aminomethyl)aniline (50 mg), tetrakistriphenylphosphine palladium (18 mg), potassium carbonate (24 mg), 2-chloro-6-methoxypyridine (25 mg) and toluene (3 ml) was heated under reflux under nitrogen atmosphere for 16 h and, thereafter, ethyl acetate and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=1:4) to give 54.5 mg of the titled compound (yield, 82%).

¹H-NMR (CDCl₃) δ: 1.45(18H, s), 3.91(3H, s), 4.77(2H, s), 6.19(1H, d, J=7.9 Hz), 6.36(1H, brs), 6.39(1H, d, J=7.9 Hz), 6.93(1H, d, J=6.9 Hz) 7.23-7.30(3H, m), 7.39(1H, dd, J=7.9, 7.9 Hz)

The procedure of Example 39 was repeated using corresponding aniline derivatives and corresponding halogenated derivatives to give the compounds shown in Tables 65-73 (under “Reaction conditions” in the tables: palladium Pd:(1) is tetrakistriphenylphosphine palladium, Pd:(2) is tris(dibenzylideneacetone)dipalladium, base:(1) is potassium t-butoxide, base:(2) is sodium t-butoxide, base:(3) is potassium carbonate; ligand:(1) is diphenylphosphino-ferrocene and ligand:(2) is 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.

TABLE 65 Aniline Halogentaed Reaction Example derivative derivative Product conditions Spectral data 41

Pd: (1) base: (3) ¹H-NMR(CDCl₃)1.47(18H, s), 4.78(2H, s), 6.71(1H, brs ), 6.81(1H, dd, J=7.6, 4.3Hz), 7.02(1H, d, J=7.6Hz), 7.29 (1H, dd, J=7.6, 7.6Hz), 7.43(1H, s), 7.49(1H, d, J=7.6Hz ), 7.79(1H, d, J=7.6Hz), 8.33(1H, d, J=4.3Hz) 43

Pd: (1) base: (3) ¹H-NMR(CDCl₃)δ1.45(18H, s), 3.88(3H, s), 3.97(3H, s), 4.78(2H, s), 6.14(1H, d, J=8.8Hz), 6.95(1H, d, J=7.6Hz), 7.26(1H, dd, J=7.6, 7.6Hz), 7.59(1H, d, J=7.6Hz), 7.66( 1H, s), 8.10(1H, d, J=8.8Hz), 10.42(1H, brs) 421

Pd: (1) base: (3) ¹H-NMR(CDCl₃)δ8.27(1H, d, J=8.9Hz), 7.45-7.30(3H, m), 7.16-7.06(2H, m), 6.32(1H, d, J=8.9Hz), 4.79(2H, s), 4.09(3H, s), 1.46(18H, s) 422

Pd: (1) base: (3) ¹H-NMR(CDCl₃)δ11.00(1H, brs), 8.46(1H, d, J=9.2Hz), 8.28(1H, d, J=8.3Hz), 7.28(1H, dd, J=8.3, 7.9Hz), 6.99 (1H, d, J=7.9Hz), 6.28(1H, d, J=9.2Hz), 4.95(2H, s), 3.95 (3H, s), 1.46(18H, s)

TABLE 66 Aniline Halogenated Reaction Example derivative derivative Product conditions Spectral data 423

Pd: (2) base: (2) ligand: (2) ¹H-NMR(CDCl₃)δ7.38(1H, brs), 7.34-7.27(2H, m), 6.96(1H, d, J=6.6Hz), 6.89(1H, s), 6.74(1H, s), 6.51(1H, s), 4.83(1H , brs), 4.31(2H, d, J=5.6Hz), 3.94(3H, s), 3.90(3H, s), 1.46 (9H, s) 424

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ8.27(1H, d, J=5.6Hz), 7.58(1H, s), 7.55( 1H, d, J=7.9Hz), 7.28(1H, dd, J=7.9, 7.3Hz), 7.10(1H, brs), 6.94(1H, d, J=7.3Hz), 6.61(1H, d, J=5.6Hz), 4.83(1H, brs), 4.32(2H, d, J=5.6Hz), 2.42(3H, s), 1.47(9H, s) 425

Pd: (1) base: (3) ¹H-NMR(CDCl₃)δ1.39(3H, t, J=6.9Hz), 1.47(18H, s), 4.39( 2H, q, J=6.9Hz), 4.79(2H, s), 6.20(1H, d, J=8.9Hz), 7.11( 1H, d, J=7.6Hz), 7.32(1H, dd, J=7.6, 7.6Hz), 7.53(1H, s), 7.57(1H, d, J=7.6Hz), 8.41(1H, d, J=8.9Hz), 10.61(1H, brs) 426

Pd: (1) base: (3) ¹H-NMR(CDCl₃)δ1.46(18H, s), 3.90(3H, s), 4.77(2H, s), 6.22(1H, d, J=8.6Hz), 6.73(1H, brs), 6.99(1H, d, J=7.6Hz), 7.26(1H, dd, J=7.6, 7.6Hz), 7.44(1H, s), 7.49(1H, d, J=7.6 Hz), 7.66(1H, d, J=8.6Hz)

TABLE 67 Aniline Halogenated Reaction Example derivative derivative Product conditions Spectral data 427

Pd: (1) base: (1) ¹H-NMR(CDCl₃)δ1.46(9H, s), 3.83(3H, s), 4.32(2H, d, J=5.9 Hz), 4.88(1H, brt), 7.03-7.12(3H, m), 7.15(1H, s), 7.23 (1H, s), 7.34(1H, dd, J=7.6, 7.6Hz), 7.63(1H, d, J=3.0Hz), 9.30(1H, brs) 428

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.44(9H, s), 2.09(3H, s), 4.24(2H, d, J=5.9 Hz), 4.80(1H, brt), 6.64(1H, d, J=7.9Hz), 6.66(1H, s), 6.87 (1H, d, J=7.6), 7.08(1H, dd, J=7.9, 7.9Hz), 7.19(1H, dd, J= 7.6, 7.6Hz), 7.43(1H, d, J=7.6Hz), 7.97(1H, d, J=7.9Hz), 8.24(1H, brs) 429

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.37(9H, s), 1.63(6H, s), 2.24(3H, s), 4.99 (1H, brs), 6.56(1H, d, J=5.0Hz), 6.70(1H, s), 6.74(1H, brs ), 7.09(1H, d, J=7.3Hz), 7.20-7.31(3H, m), 8.05(1H, d, J= 5.0Hz) 430

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ0.92(3H, t, J=7.3Hz), 1.42(9H, s), 1.66- 1.82(2H, m), 2.26(3H, s), 4.43-4.60(1H, m), 4.77-4.87(1H, m), 6.52(1H, brs), 6.58(1H, d, J=5.0Hz), 6.68(1H, s), 6.94 (1H, d, J=6.6Hz), 7.17(1H, s), 7.23-7.32(2H, m), 8.06(1H, d, J=5.0Hz)

TABLE 68 Aniline Halogenated Reaction Example derivative derivative Product conditions Spectral data 431

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.46(18H, s), 2.19(3H, s), 2.20(3H, s), 4.83(2H, s), 6.21(1H, brs), 6.27(1H, s), 6.52(1H, d, J=5.0 Hz), 6.60(1H, d, J=7.6Hz), 6.99(1H, d, J=7.6Hz), 7.18(1H, dd, J=7.6, 7.6Hz), 7.24(1H, s), 8.02(1H, d, J=5.0Hz) 432

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.23(3H, t, J=7.3Hz), 1.46(9H, s), 2.25( 3H, s), 2.64(2H, q, J=7.3Hz), 4.33(2H, q, J=5.3Hz), 4.71(1H , brt), 6.44(1H, brs), 6.56(1H, d, J=5.3Hz), 6.64(1H, s), 7.14-7.26(3H, m), 8.04(1H, d, J=5.3Hz) 433

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.44(3H, t, J=6.9Hz), 1.44(9H, s), 2.22( 3H, s), 4.06(2H, q, J=6.9Hz), 4.31(2H, d, J=5.6Hz), 5.02( 1H, brt), 6.31(1H, brs), 6.50(1H, s), 6.51(1H, d, J=5.3Hz), 6.83(1H, d, J=8.6Hz), 7.16-7.23(2H, m), 8.01(1H, d, J=5.3 Hz) 434

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.44(9H, s), 2.22(3H, s), 2.78-2.86(2H, m), 3.25-3.34(2H, m), 4.78(1H, brt), 6.54(1H, d, J=5.3Hz), 6.58(1H, s), 6.86(1H, brs), 7.01-7.13(1H, m), 7.17-7.28( 2H, m), 7.66-7.75(1H, m), 8.03(1H, d, J=5.3Hz)

TABLE 69 Aniline Halogenated Reaction Example derivative derivative Product conditions Spectral data 435

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.46(9H, s), 2.29(3H, s), 4.42(2H, d, J=5.6 Hz), 4.96(1H, brt), 6.66(1H, d, J=5.0Hz), 6.69(1H, s), 6.81 (1H, brs), 7.02(1H, d, J=7.3Hz), 7.23(1H, dd, J=7.3, 7.3Hz ), 7.96(1H, d, J=7.3Hz), 8.12(1H, d, J=5.0Hz) 436

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.36(9H, brs), 1.80-1.95(1H, m), 2.01- 2.17(1H, m), 2.45-2.60(4H, m), 5.09(1H, brs), 6.56(1H, brs), 6.57(1H, d, J=5.3Hz), 6.70(1H, s), 7.11(1H, d, J=7.3 Hz), 7.22-7.31(3H, m), 8.05(1H, d, J=5.3Hz) 437

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.44(9H, s), 2.25(3H, s), 2.72-2.79(2H, m), 3.32-3.42(2H, m), 4.56(1H, brt), 6.47(1H, brs), 6.56( 1H, d, J=4.9Hz), 6.65(1H, s), 7.10-7.19(2H, m), 7.22-7.30( 2H, m), 8.05(1H, d, J=4.9Hz) 438

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.40(3H, t, J=6.9Hz), 1.44(18H, s), 2.28( 3H, s), 3.91(2H, q, J=6.9Hz), 4.89(2H, s), 6.60(1H, d, J=5.0 Hz), 6.68(1H, s), 6.77(1H, s), 6.79(1H, d, J=7.9Hz), 7.05( 1H, dd, J=7.9, 7.9Hz), 7.77(1H, d, J=7.9Hz), 8.09(1H, d, J= 5.0Hz)

TABLE 70 Aniline Halogenated Reaction Example derivative derivative Product conditions Spectral data 439

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.44(18H, s), 2.26(3H, s), 4.88(2H, s), 6.45(1H, brs), 6.59(1H, d, J=5.3Hz), 6.62(1H, s), 7.08(1H, s), 7.25-7.29(2H, m), 8.05(1H, d, J=5.3Hz) 440

Pd: (1) base: (3) ¹H-NMR(CDCl₃)δ1.45(18H, s), 3.93(3H, s), 4.78(2H, s), 6.22(1H, d, J=8.6Hz), 7.00(1H, s), 7.03(1H, d, J=7.6Hz), 7.29(1H, dd, J=7.6, 7.6Hz), 7.46(1H, d, J=7.6Hz), 7.54(1H, s), 7.62(1H, d, J=8.6Hz) 441

Pd: (2) base: (2) ligand: (1) ¹H-NMR(CDCl₃)δ1.47(9H, s), 4.32(2H, d, J=5.6Hz), 4.86( 1H, brs), 6.71(1H, dd, J=7.6, 5.0Hz), 6.97(1H, d, J=7.6Hz), 6.98(1H, s), 7.30(1H, dd, J=7.6, 7.6Hz), 7.52-7.50(3H, m), 8.12(1H, dd, J=5.0, 1.7Hz) 442

Pd: (1) base: (3) ¹H-NMR(CDCl₃)δ1.47(9H, s), 3.89(3H, s), 3.98(3H, s), 4.32 (2H, d, J=5.4Hz), 4.81(1H, brt), 6.15(1H, d, J=8.5Hz), 6.96 (1H, d, J=8.3Hz), 7.28(1H, dd, J=8.3, 8.3Hz), 7.57(1H, d, J= 8.3Hz), 7.77(1H, s), 8.11(1H, d, J=8.5Hz), 10.47(1H, s)

TABLE 71 Aniline Halogenated Reaction Example derivative derivative Product conditions Spectral data 497

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.46(18H, s), 2.23(3H, s), 4.76(2H, s), 6.50(1H, brs), 6.83(1H, d, J=6.9Hz), 6.93(1H, d, J=6.9Hz), 7.15-7.36(4H, m), 8.02(1H, s) 498

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.46(9H, s), 2.24(3H, s), 4.30(2H, d, J=5.6 Hz), 4.83(1H, brt), 6.13(1H, brs), 6.72(1H, dd, J=7.3, 5.0 Hz), 6.91(1H, d, J=7.3Hz), 7.27(1H, dd, J=7.6, 7.6Hz), 7.36 (1H, d, J=7.6Hz), 7.46(1H, s), 7.48(1H, d, J=7.6Hz), 8.11( 1H, dd, J=5.0Hz) 499

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.43(18H, s), 2.20(3H, s), 3.82(3H, s), 4.81(2H, s), 6.27(1H, brs), 6.46(1H, s), 6.50(1H, d, J=5.3 Hz), 6.84(1H, d, J=8.9Hz), 7.00(1H, d, J=2.3Hz), 7.18(1H, dd, J=8.9, 2.3Hz), 8.00(1H, d, J=5.3Hz) 500

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.44(9H, s), 2.29(3H, s), 4.11(2H, d, J=6.6 Hz), 5.72(1H, brt), 6.43-6.46(1H, m), 6.60-6.73(3H, m), 7.24(1H, d, J=8.6Hz), 7.39-7.45(1H, m), 7.41(1H, s), 7.50- 7.58(1H, m), 7.64(1H, d, J=2.0Hz), 7.72(1H, d, J=1.3Hz), 8.09(1H, d, J=5.3Hz)

TABLE 72 Aniline Halogenated Reaction Example derivative derivative Product conditions Spectral data 505

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ8.09(1H, d, J=5.3Hz), 7.80(1H, d, J=7.9Hz), 7.05(1H, dd, J=7.9, 7.9Hz), 6.83-6.72(2H, m), 6.66(1H, s), 6.59(1H, d, J=5.3Hz), 4.90(2H, s), 3.78(2H, t, J=6.6Hz), 2.28 (3H, s), 1.90-1.75(2H, m), 1.44(18H, s), 1.06(3H, t, J=7.4Hz) 519

Pd: (2) base: (1) ligand (1) ¹H-NMR(CDCl₃)δ1.45(3H, t, J=6.9Hz), 1.45(9H, s), 2.29(3H, s), 3.94(2H, q, J=6.9Hz), 4.52(1H, d, J=5.6Hz), 4.94(1H, brt ), 6.58(1H, s), 6.62(1H, d, J=5.0Hz), 6.74(1H, brs), 7.12(1H, d, J=8.9Hz), 8.00(1H, d, J=8.9Hz), 8.10(1H, d, J=5.0Hz) 520

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ1.40(3H, t, J=6.9Hz), 1.45(9H, s), 2.26(3H, s), 2.35(3H, s), 3.88(2H, q, J=6.9Hz), 4.39(2H, d, J=5.0Hz), 4.76(1H, brs), 6.58(1H, d, J=5.3Hz), 6.61(1H, s), 6.93(1H, d, J=8.2Hz), 7.65(1H, d, J=8.2Hz), 8.07(1H, d, J=5.3Hz)

TABLE 73 Aniline Halogenated Reaction Example derivative derivative Product conditions Spectral data 540

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ8.10(1H, d, J=5.3Hz), 7.80(1H, d, J=7.3 Hz), 7.06(1H, dd, J=8.6, 7.3Hz), 6.81(1H, s), 6.77(1H, d, J=8.6Hz), 6.69(1H, s), 6.60(1H, d, J=5.3Hz), 4.89(2H, s), 3.75(3H, s), 2.28(3H, s), 1.45(18H, s) 542

Pd: (2) base: (1) ligand: (1) ¹H-NMR(CDCl₃)δ8.09(1H, d, J=5.3Hz), 7.74(1H, d, J=7.6Hz ), 7.04(1H, dd, J=8.6, 7.6Hz), 6.80(1H, d, J=8.6Hz), 6.74( 1H, s), 6.67(1H, s), 6.58(1H, d, J=5.3Hz), 4.88(2H, s), 4.19 -4.07(1H, m), 2.27(3H, s), 1.43(18H, s), 1.29(6H, d, J=6.3 Hz)

Example 45 Synthesis of 2-(3-aminomethylphenylamino)-6-methoxynicotinic acid hydrochloride

A mixture of the compound (37 mg) obtained in Example 43, potassium hydroxide (96 mg), water (2 ml) and 1,4-dioxane (2 ml) was heated at 60° C. for 2 h. The reaction mixture was cooled, then rendered acidic with 2 N HCl and subjected to extraction with methylene chloride. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was worked up as in Example 2 to give the titled compound quantitatively.

¹H-NMR (DMSO-d₆) δ: 3.95(3H, s), 4.01(2H, brs), 6.27(1H, d, J=8.6 Hz), 7.14(1H, d, J=7.6 Hz), 7.39(1H, dd, J=8.3, 7.6 Hz), 7.71(1H, s), 7.90(1H, d, J=8.3 Hz), 8.14(1H, d, J=8.6 Hz), 8.30(3H, brs), 10.75 (1H, s), 13.06(1H, brs)

Example 52 Synthesis of 2-(3-aminomethylphenylamino)-6-methyl-3-nitropyridine hydrochloride

A mixture of the compound (118 mg) obtained in Example 446, concentrated sulfuric acid (1 ml) and water (2 ml) was heated at 120° C. for 4 h. The reaction mixture was put into ice water, adjusted to pH 8 with saturated sodium hydrogencarbonate and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and dried under reduced pressure. The resulting residue was dissolved in methanol (2 ml) and, after addition of a 1,4-dioxane solution (4 N, 0.5 ml) of hydrogen chloride at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give 37.1 mg of the titled compound (61%).

¹H-NMR (DMSO-d₆) δ: 2.49(3H, s), 4.03(2H, q, J=5.6 Hz), 6.90(1H, d, J=8.6 Hz), 7.27(1H, d, J=7.9 Hz), 7.42(1H, dd, J=7.9, 7.9 Hz), 7.77 (1H, s), 7.86(1H, d, J=7.9 Hz), 8.31(3H, brs), 8.45 (1H, d, J=8.6 Hz), 10.09(1H, s)

Example 53 Synthesis of 2-(3-aminomethylphenylamino)-6-ethyl-3-nitropyridine hydrochloride

Using the compound obtained in Example 447 as a starting material, the procedure of Example 52 was repeated to give the titled compound (yield, 85%).

¹H-NMR (DMSO-d₆) δ: 1.24(3H, t, J=7.3 Hz), 2.79(2H, q, J=7.3 Hz), 4.02(2H, q, J=5.0 Hz), 6.92(1H, d, J=8.6 Hz), 7.26(1H, d, J=7.6 Hz), 7.43 (1H, dd, J=7.6, 7.6 Hz), 7.75(1H, s), 7.90(1H, d, J=7.6 Hz), 8.41(3H, brs), 8.48(1H, d, J=8.6 Hz), 10.10(1H, s)

Example 443 Synthesis of 2-(3-(t-butoxycarbonylaminomethyl)phenylamino)-6-methoxy-isonicotinic acid

To a mixture of the compound (53.8 mg) obtained in Example 423 and methanol (3 ml), a 2N aqueous sodium hydroxide solution (1 ml) was added. The reaction mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. To the resulting residue, ethyl acetate was added and mixture was subjected to extraction with water. The aqueous layer was adjusted to pH 1 with 2N HCl and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 47.3 mg of the titled compound (yield, 90%).

¹H-NMR(CDCl₃) δ: 7.49(1H, d, J=7.9 Hz), 7.45(1H, s), 7.28(1H, dd, J=7.9, 7.3 Hz), 6.98(1H, s), 6.93(1H, d, J=7.3 Hz), 6.76(1H, s), 4.92(1H, brs), 4.31(2H, d, J=5.6 Hz), 3.95(3H, s), 1.46(9H, s)

Example 444 Synthesis of 2-(3-(t-butoxycarbonylaminomethyl)phenylamino)-4-hydroxymethyl-6-methoxypyridine

To a mixture of the compound (155.3 mg) obtained in Example 423, tetrahydrofuran (4 ml) and methanol (2 ml), lithium borohydride (13 mg) was added. The reaction mixture was stirred at room temperature for one week and, after addition of water, the mixture was concentrated under reduced pressure. Water was added to the resulting residue and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:1) to give 86.1 mg of the titled compound (yield, 60%).

¹H-NMR(CDCl₃) δ: 7.37(1H, s), 7.18-7.12(2H, m), 6.93-6.88(1H, m), 6.42(1H, s), 6.42(1H, s), 6.18(1H, s), 4.88(1H, brs), 4.59(2H, s), 4.29(2H, d, J=5.6 Hz), 3.90(3H, s), 1.45(9H, s)

Example 446 Synthesis of 2-(2-(3-(di-(t-butoxycarbonyl)aminomethyl)phenylamino)-3-nitropyridine-6-yl)malonic acid dimethyl ester

To a mixture of the compound (150 mg) obtained in Example 27, dimethyl malonate (50 mg) and dimethyl-formamide (3 ml), sodium hydride (content, 60%; 15 mg) was added. The reaction mixture was stirred at room temperature for 3 h and then ethyl acetate and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 123 mg of the titled compound (yield, 68%).

¹H-NMR(CDCl₃) δ: 1.47(18H, s), 3.76(6H, s), 4.81(2H, s), 4.91(1H, s), 6.95(1H, d, J=8.6 Hz), 7.08(1H, d, J=7.9 Hz), 7.32(1H, dd, J=7.9, 7.9 Hz), 7.44(1H, s), 7.68(1H, d, J=7.9 Hz), 8.54(1H, d, J=8.6 Hz), 10.18(1H, brs)

The procedure of Example 446 was repeated using corresponding chlorinated derivatives forms and corresponding reagents to give the compounds listed in Table 74.

TABLE 74 Example Chlorinated derivative Reagent Product Spectral data 447

CH₃CH(CO₂Et)₂

¹H-NMR(CDCl₃)δ1.15-1.23(6H, m), 1.47(18H, s), 1.85(3H, s), 4.10-4.40(4H, m), 4.81(2H, s), 6.97(1H, d, J=8.9Hz), 7.07(1H, d, J=7.6Hz), 7.31(1H, dd, J=7.6, 7.6Hz), 7.34(1H, d, J=2.0Hz), 7.62-7.69(1H, m), 8.51(1H, d, J=8.9Hz), 10.17(1H, brs) 448

MeSH

¹H-NMR(CDCl₃)δ1.47(9H, s), 2.53(3H, s), 4.35(2H, d, J=5.6Hz ), 4.85(1H, brt), 6.68(1H, d, J=8.9Hz), 7.10(2H, d, J=7.6Hz), 7.34(1H, dd, J=7.6, 7.6Hz), 7.52(1H, d, J=7.6Hz), 7.60(1H, s), 8.27(1H, d, J=8.9Hz), 10.45(1H, brs)

Example 449 Synthesis of 2-(3-(t-butoxycarbonylaminomethyl)phenylamino)-4-methylpyridine

A mixture of 3-(di-(t-butoxycarbonyl)aminomethyl)bromobenzene (260 mg), tris(dibenzylideneacetone)dipalladium (42 mg), diphenylphosphinoferrocene (50 mg), potassium t-butoxide (102 mg), 2-amino-4-methylpyridine (108 mg) and toluene (10 ml) was heated under a nitrogen atmosphere at 80° C. for 22 h. Ethyl acetate and water were added to the reaction mixture. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:1) to give 29.2 mg of the titled compound (yield, 10%).

¹H-NMR(CDCl₃) δ: 1.46(9H, s), 2.26(3H, s), 4.30(2H, d, J=5.9 Hz), 4.90(1H, brt), 6.59(1H, d, J=5.0 Hz), 6.60(1H, s), 6.68(1H, s), 6.94(1H, d, J=6.3 Hz), 7.21-7.31(3H, m), 8.06(1H, d, J=5.0 Hz)

The procedure of Example 449 was repeated using corresponding amine derivatives to give the compounds listed in Table 75.

TABLE 75 Amine Example derivative Product Spectral data 450

¹H-NMR(CDCl₃)δ1.46(9H, s), 2.22(3 H, s), 2.40(3H, s), 4.30(2H, d, J=5.6 Hz), 4.83(1H, brt), 6.43(1H, brs), 6.47(1H, s), 6.53(1H, s), 6.93(1H, d, J=7.3Hz), 7.19-7.29(3H, m) 451

¹H-NMR(CDCl₃)δ1.21(3H, t, J=7.6Hz ), 1.46(9H, s), 2.56(2H, q, J=7.6Hz ), 4.30(2H, d, J=5.6Hz), 4.83(1H, brt), 6.54(1H, brs), 6.61(1H, d, J= 5.0Hz), 6.69(1H, s), 6.91-6.95(1H, m), 7.18-7.31(3H, m), 8.09(1H, d, J= 5.0Hz)

Example 452 Synthesis of 2-(3-(t-butoxycarbonylaminomethyl)phenylamino)-6-methoxynicotinic acid

obtained in Example 442 as a starting material, the procedure of Example 45 was repeated to give the titled compound (yield, 92%).

¹H-NMR(CDCl₃—CD₃OD) δ: 1.46(9H, s), 3.99(3H, s), 4.30(2H, s), 6.16(1H, d, J=8.6 Hz), 6.94(1H, d, J=7.8 Hz), 7.28(1H, dd, J=7.8, 7.8 Hz), 7.58(1H, d, J=7.8 Hz), 7.73(1H, s), 8.16(1H, d, J=8.6 Hz)

Example 453 Synthesis of 2-(3-t-butoxycarbonylaminomethyl)phenylamino)-6-methoxynicotinamide

To a mixture of the compound (44 mg) obtained in Example 452, triethylamine (18 mg) and tetrahydrofuran (2 ml), ethyl chlorocarbonate (14.3 mg) was added and the resulting mixture was stirred at room temperature for 15 min. Ammonia gas was blown through the reaction mixture at room temperature and after stirring at room temperature for 5 min, the mixture was concentrated under reduced pressure. To the resulting residue, a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was subjected to extraction with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (eluent, methanol:methylene chloride=1:20) to give 10 mg of the titled compound (yield, 11%).

¹H-NMR(DMSO-d₆) δ: 1.39 (9H, s), 3.92(3H, s), 4.12(2H, d, J=5.9 Hz), 6.20(1H, d, J=8.6 Hz), 6.85(1H, d, J=7.6 Hz), 7.24(1H, dd, J=7.6, 7.6 Hz), 7.32-7.40(2H, m), 7.51(1H, d, J=7.6 Hz), 7.61(1H, s), 8.01(1H, brs), 8.10(1H, d, J=8.6 Hz)

Example 454 Synthesis of 2-(3-(t-butoxycarbonylaminomethyl)phenylamino)-3-hydroxymethyl-6-methoxypyridine

To a mixture of the compound (300 mg) obtained in Example 452, triethylamine (101 mg) and tetrahydrofuran (8 ml), a tetrahydrofuran solution (1 ml) of ethyl chlorocarbonate (109 mg) was added under ice cooling and the resulting mixture was stirred at 0° C. for 15 min. The reaction mixture was filtered and a tetrahydrofuran solution (2 M, 0.8 ml) of lithium borohydride was added to the filtrate under ice cooling. The reaction mixture was stirred at 0° C. for 30 min and thereafter a 1 N aqueous sodium hydroxide solution was added under ice cooling. Further, the reaction mixture was stirred at 0° C. for 5 min and then ether and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:methylene chloride=1:10) to give 199 mg of the titled compound (yield, 69%).

¹H-NMR(CDCl₃) δ: 1.46(9H, s), 3.93(3H, s), 4.31(2H, d, J=5.6 Hz), 4.67(2H, d, J=5.6 Hz), 4.79(1H, brt), 6.15(1H, d, J=7.9 Hz), 6.89(1H, d, J=7.6 Hz), 7.21-7.31(3H, m), 7.48(1H, d, J=7.6 Hz), 7.64(1H, brs), 7.70(1H, brs)

Example 456 Synthesis of 2-(3-(t-butoxycarbonylaminomethyl)phenylamino)-6-methoxypyridine-3-carboaldehyde

A mixture of the compound (24 mg) obtained in Example 454, manganese tetraoxide (40 mg) and benzene (8 ml) was stirred at room temperature for 2 days.

The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:methylene chloride=1:20) to give 14 mg of the titled compound (yield, 59%).

¹H-NMR(CDCl₃) δ: 1.47(9H, s), 4.01(3H, s), 4.33(2H, d, J=5.6 Hz), 4.82(1H, brt), 6.24(1H, d, J=8.3 Hz), 7.00(1H, d, J=7.6 Hz), 7.30(1H, dd, J=7.6, 7.6 Hz), 7.61(1H, d, J=7.6 Hz), 7.71(1H, d, J=8.3 Hz), 7.72(1H, s), 9.67(1H, s), 10.95(1H, s)

Example 472 Synthesis of 2-(3-aminomethylphenylamino)-4-hydroxymethyl-6-methoxypyridine dihydrochloride

To a mixture of the compound (109.5 mg) obtained in Example 423, tetrahydrofuran (4 ml) and methanol (1 ml), lithium borohydride (19 mg) was added. The reaction mixture was stirred at room temperature for 44 h and after addition of 2 N HCl, the resulting mixture was concentrated under reduced pressure. The resulting residue was subjected to basic silica gel column chromatography (eluent, methanol:methylene chloride=1:19). To a mixture of the purified product and methanol (3 ml), a 1,4-dioxane solution (4 N, 0.3 ml) of hydrogen chloride was added and the resulting mixture was concentrated under reduced pressure. The resulting residue was recrystallized from methanol-ethyl acetate to give 48 mg of the titled compound (yield, 58%).

¹H-NMR(DMSO-d₆) δ: 9.18(1H, brs), 8.39(3H, brs), 7.78(1H, s), 7.61(1H, d, J=7.9 Hz), 7.29(1H, dd, J=7.9, 7.3 Hz), 7.08(1H, brs), 7.02(1H, d, J=7.3 Hz), 6.47(1H, s), 6.11(1H, s), 4.42(2H, s), 3.94(2H, q, J=5.6 Hz), 3.87(3H, s)

Example 507 Synthesis of 2-(3-(t-butoxycarbonylaminomethyl)phenylamino)-5-methylthiazole

To a mixture of propionaldehyde (72 μl), chloroform (1 ml) and 1,4-dioxane (1 ml), bromine (52 μl) was added. The reaction mixture was stirred at room temperature for 30 min and then N-(3-(t-butoxycarbonylaminomethyl)phenyl)thiourea (262 mg), acetone (2 ml) and triethylamine (0.14 ml) were added. The reaction mixture was heated under reflux for 3.5 h and concentrated under reduced pressure. To the resulting residue, water was added and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (eluent, methylene chloride:methanol=99:1) to give 79.2 mg of the titled compound (yield, 27%).

¹H-NMR(CDCl₃) δ: 7.30-7.22(4H, m), 7.17(1H, d, J=7.6 Hz), 6.91(1H, d, J=1.0 Hz), 4.94(1H, brs), 4.30(2H, d, J=5.6 Hz), 2.34(3H, d, J=1.0 Hz), 1.47(9H, s)

Example 508 Synthesis of 2-(3-aminomethylphenylamino)-5-methylthiazole

A mixture of the compound (73 mg) obtained in Example 507 and trifluoroacetic acid (5 ml) was stirred at room temperature for 1 h and concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (eluent, methylene chloride:methanol=95:5) to give 34.5 mg of the titled compound (yield, 67%).

¹H-NMR(CDCl₃) δ: 7.32-7.28(3H, m), 7.19(1H, d, J=7.3 Hz), 6.97(1H, d, J=7.3 Hz), 6.92(1H, d, J=1.0 Hz), 3.87(2H, s), 2.35(3H, d, J=1.0 Hz), 1.76(2H, brs)

Example 509 Synthesis of 2-(3-(t-butoxycarbonylaminomethyl)phenylamino)-4-methylthiazole Example 511 Synthesis of 2-(3-(di-(t-butoxycarbonyl)aminomethyl)phenylamino)-5-methyloxazole

To a mixture of 3-(di-(t-butoxycarbonyl)aminomethyl)aniline (200 mg), dimethylaminopyridine (166 mg) and methylene chloride (10 ml), thiophosgene (45 μl) was added under ice cooling and the resulting mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:3) to give N-(3-(di-(t-butoxycarbonyl)aminomethyl)phenyl)isothiocyanate.

A mixture of the thus obtained compound (193 mg), 1-azido-propane-2-one (81 mg), triphenylphosphine (217 mg) and methylene chloride (5 ml) was stirred at room temperature for 15 h and then oxalic acid (115 mg) was added at room temperature. The reaction mixture was heated under stirring at 60° C. for 30 min and concentrated under reduced pressure. To the resulting residue, ethyl acetate and a 2 N aqueous sodium hydroxide solution were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:10) to give 78 mg of the titled compound (yield, 33%).

¹H-NMR(CDCl₃) δ: 1.45(18H, s), 2.25(3H, d, J=1.0 Hz), 4.77(2H, s), 6.51(1H, d, J=1.0 Hz), 6.91(1H, d, J=7.6 Hz), 7.15(1H, brs), 7.22-7.26(1H, m), 7.25(1H, dd, J=7.6, 7.6 Hz), 7.40(1H, d, J=7.6 Hz)

The procedure of Example 511 was repeated using corresponding reagents to give the compounds shown in Table 76.

TABLE 76 Aniline Example derivative Product Spectral data 512

¹H—NMR(CDCl₃)δ1.43(18H, s), 1.46( 3H, t, J=6.9Hz), 2.27(3H, d, J=1.0Hz), 3.93(2H, q, J=6.9Hz), 4.88(2H, s), 6.52(1H, d, J=1.0Hz), 6.77(1H, d, J= 7.6Hz), 7.08(1H, dd, J=7.6, 7.6Hz), 7.19(1H, s), 8.02(1H, d, J=7.6Hz) 513

¹H—NMR(CDCl₃)δ1.44(18H, s), 2.21( 3H, s), 2.24(3H, s), 4.82(2H, s), 6.48( 1H, s), 6.88(1H, d, J=7.9Hz), 7.19(1H, dd, J=7.9, 7.9Hz), 7.77(1H, d, J=7.9Hz ) 514

¹H—NMR(CDCl₃)δ1.44(18H, s), 2.23( 3H, s), 3.79(3H, s), 4.80(2H, s), 6.46( 1H, s), 6.81(1H, d, J=8.9Hz), 6.97(1H, d, J=2.3Hz), 7.45(1H, dd, J=8.9, 2.3Hz )

Example 515 Synthesis of 2-(3-aminomethyl)phenylamino)-5-methyloxazole trifluoroacetic acid salt

A mixture of the compound (292 mg) obtained in Example 511 and trifluoroacetic acid (2 ml) was stirred at room temperature for 2 h and concentrated under reduced pressure. The resulting residue was recrystallized from ethanol/ethyl acetate/n-hexane to give 119 mg of the titled compound (38%).

¹H-NMR(DMSO-d₆) δ: 2.24(3H, s), 3.98(2H, q, J=5.6 Hz), 6.59(1H, s), 7.00(1H, d, J=7.3 Hz), 7.32(1H, dd, J=7.3, 7.3 Hz), 7.53(1H, d, J=7.3 Hz), 7.67(1H, s), 8.16(3H, brs), 10.08(1H, s)

The procedure of Example 515 was repeated using corresponding reagents to give the compounds listed in Table 77.

TABLE 77 Example Reagent Product Spectral data 516

¹H—NMR(DMSO-d₆)δ1.37(3H, t, J=6.9 Hz), 2.24(3H, s), 3.89(2H, q, J=6.9 Hz), 4.05(2H, q, J=5.6Hz), 6.63(1H, s), 7.08(1H, d, J=7.9Hz), 7.15(1H, dd, J=7.9, 7.9Hz), 8.13(1H, d, J=7.9 Hz), 8.18(3H, brs), 9.33(1H, brs) 517

¹H—NMR(DMSO-d₆)δ2.22(3H, s), 2.33 (3H, s), 4.05(2H, q, J=5,6Hz), 6.60( 1H, s), 7.12(1H, d, J=7.9Hz), 7.24( 1H, dd, J=7.9, 7.9Hz), 7.75(1H, d, J= 7.9Hz), 8.18(3H, brs), 9.40(1H, brs ) 518

¹H—NMR(DMSO-d₆)δ2.22(3H, s), 3.80 (3H, s), 3.94(2H, q, J=5.6Hz), 6.55( 1H, s), 7.02(1H, d, J=8.9Hz), 7.54( 1H, dd, J=8.9, 2.3Hz), 7.59(1H, d, J= 2.3Hz), 8.00(3H, brs), 9.87(1H, s)

Example 523 Synthesis of 2-(3-aminomethylphenylamino)-3,5-dinitropyridine

A mixture of 3-aminobenzylamine (696 mg), dimethylaminopyridine (674 mg), 3-nitrophenyloxycarbonyl-Wang resin (2.85 g; Tetrahedron Lett., Vol, 37, 937 (1996)) and tetrahydrofuran (60 ml) was stirred at room temperature for 24 h and then filtered. The resulting resin was washed sequentially with dimethylformamide, water, methanol and methylene chloride and then dried under reduced pressure to give 3-aminobenzylaminocarbonyl-Wang resin.

A mixture of the thus obtained resin (100 mg, 0.071 mol), potassium carbonate (100 mg), 2-chloro-3,5-dinitropyridine (72 mg), palladium (II) acetate (16 mg), diphenylphosphinoferrocene (79 mg) and acetonitrile (9 ml) was stirred under a nitrogen atmosphere at 80° C. and then filtered. The resulting resin was washed sequentially with dimethylformamide, water, methanol and methylene chloride, dried under reduced pressure and, after adding trifluoroacetic acid, the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the resulting residue, water and ethyl acetate were added. The aqueous layer was washed with ethyl acetate and concentrated under reduced pressure. The resulting residue was purified with Sep-PaK® Plus C18 Cartridges (Waters) to give 1.7 mg of the titled compound (8%).

¹H-NMR(CD₃OD) δ: 4.16(2H, s), 7.35(1H, d, J=7.9 Hz), 7.53(1H, dd, J=7.9, 7.9 Hz), 7.75(1H, d, J=7.9 Hz), 7.80(1H, s), 9.25(1H, d, J=2.4 Hz), 9.30(1H, d, J=2.4 Hz)

The procedure of Example 523 was repeated using corresponding chlorinated derivatives to give the compounds listed in Tables 78-80.

TABLE 78

Chlorinated Example derivative Product Spectral data 524

¹H—NMR(CD₃OD)2.35(3H, s), 2.44(3H, s), 4.13(2H, s), 6.78(1H, s), 7.19-7.50(3H, m), 7.72(1H, d, J=2.0Hz) 525

¹H—NMR(CD₃OD)4.18(2H, s), 7.33-7.46(4 H, m), 7.51(1H, d, J=7.6Hz), 7.64(1H, dd, J=7.6, 7.6Hz), 8.45(1H, d, J=5.0Hz) 526

¹H—NMR(CD₃OD)4.17(2H, s), 7.29(1H, d, J= 8.7Hz), 7.34(1H, d, J=7.6Hz), 7.39(1H, s), 7.53(1H, d, J=7.6Hz), 7.64(1H, dd, J= 7.6, 7.6Hz), 8.04(1H, dd, J=8.7, 2.0Hz), 8.61(1H, d, J=2.0Hz) 527

¹H—NMR(CD₃OD)1.47(3H, t, J=7.3Hz), 2.56 (3H, s), 4.14(2H, s), 4.48(2H, q, J=7.3 Hz), 7.27(1H, d, J=7.9Hz), 7.30(1H, s), 7.46(1H, dd, J=7.9, 7.9Hz), 7.74(1H, s), 7.75(1H, d, J=7.9Hz) 528

¹H—NMR(CD₃OD)4.12(2H, s), 7.02-7.12( 2H, m), 7.26(1H, d, J=5.2Hz), 7.37-7.42 (2H, m), 7.81(1H, s), 8.18(1H, d, J=5.2 Hz)

TABLE 79 Chlorinated Example derivative Product Spectral data 529

¹H—NMR(CD₃OD)4.15(2H, s), 6.87(1H, d, J= 8.7Hz), 7.14(1H, d, J=7.4Hz), 7.43(1H, dd, J=7.4, 6.9Hz), 7.53(1H, d, J=6.9Hz), 7.98(1H, s), 8.11(1H, J=8.7, 2.1Hz), 8.81(1H, d, J=2.1Hz) 530

¹H—NMR(CD₃OD)4.16(2H, s), 7.22(1H, d, J= 7.9Hz), 7.47(1H, dd, J=7.9, 7.9Hz), 7.65 (1H, d, J=7.9Hz), 7.92(1H, s), 8.22(1H, d, J=2.0Hz), 8.69(1H, d, J=2.0Hz) 531

¹H—NMR(CD₃OD)2.49(3H, s), 4.12(2H, s), 7.05(1H, d, J=6.2Hz), 7.15(1H, s), 7.25 (1H, s), 7.38-7.42(2H, m), 7.72(1H, s) 532

¹H—NMR(CD₃OD)4.14(2H, s), 6.82(1H, d, J= 8.9Hz), 7.10(1H, d, J=6.6Hz), 7.41-7.45 (2H, m), 8.02(1H, s), 8.11(1H, dd, J=8.9, 2.0Hz), 8.78(1H, d, J=2.0Hz) 533

¹H—NMR(CD₃OD)2.50(3H, s), 4.12(2H, s), 6.84(1H, d, J=7.6Hz), 7.20(1H, d, J=7.0 Hz), 7.40(1H, dd, J=7.0, 7.0Hz), 7.74- 7.80(2H, m), 7.87(1H, d, J=7.6Hz) 534

¹H—NMR(CD₃OD)4.15(2H, s), 7.21(1H, d, J= 7.6Hz), 7.46(1H, dd, J=7.6, 7.6Hz), 7.61 (1H, d, J=7.6Hz), 7.75(1H, s), 8.11(1H, d, J=2.6Hz), 8.35(1H, d, J=2.6Hz)

TABLE 80 Chlorinated Example derivative Product Spectral data 535

¹H—NMR(CD₃OD)4.00(3H, s), 4.12(2H, s), 6.58(1H, d, J=1.0Hz), 6.81(1H, d, J=1.0 Hz), 7.09(1H, d, J=6.9Hz), 7.37-7.43( 1H, m), 7.53(1H, d, J=6.9Hz), 7.83(1H, s) 536

¹H—NMR(CD₃OD)4.15(2H, s), 6.83-6.89( 1H, m), 6.96(1H, dd, J=7.6, 3.9Hz), 7.21 (1H, d, J=7.6Hz), 7.46(1H, dd, J=7.6, 7.6 Hz), 7.62(1H, d, J=7.6Hz), 7.76(1H, s), 8.02(1H, dd, J=7.6, 1.6Hz), 8.37(1H, dd, J=3.9, 1.6Hz) 537

¹H—NMR(CD₃OD)4.12(2H, s), 6.82(1H, d, J= 9.0Hz), 7.08(1H, d, J=7.6Hz), 7.38(1H, dd, J=7.6, 7.6Hz), 7.50(1H, d, J=7.6Hz), 7.71(1H, dd, J=9.0, 2.3Hz), 7.90(1H, s), 8.22(1H, d, J=2.3Hz) 538

¹H—NMR(CD₃OD)4.13(2H, s), 7.16(1H, d, J= 7.6Hz), 7.43(1H, dd, J=7.6, 7.6Hz), 7.64 (1H, d, J=7.6Hz), 7.84(1H, s), 7.87(1H, d, J=2.3Hz), 7.84(1H, s), 7.87(1H, d, J=2.3Hz), 8.10(1H, d, J=2.3Hz) 539

¹H—NMR(CD₃OD)2.48(3H, s), 4.13(2H, s), 6.72-6.80(2H, m), 7.35-7.42(1H, m), 7.44(1h, s), 7.51-7.60(1H, m), 7.68(1H, dd, J=7.9, 7.9Hz), 7.74(1H, s)

Several compounds used in the reactions described above are novel and the methods of synthesizing these compounds are described below as Examples 25e, 417e, 500b, 519e, 520d, 538e and 542a.

Example 25e Synthesis of 2-(5-amino-2-ethylphenyl)-2-(t-butoxycarbonylamino)indane Example 25a Synthesis of 3-cyanomethyl-4-ethylnitrobenzene

To a mixture of 3-chloromethyl-4-ethylnitrobenzene (4.0 g) and dimethyl sulfoxide (50 ml), sodium cyanide (982 mg) was added. The reaction mixture was stirred at room temperature for 3 h and then ethyl acetate, n-hexane and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.33(3H, t, J=7.6 Hz), 2.78(2H, q, J=7.6 Hz), 3.80(2H, s), 7.44(1H, d, J=8.6 Hz), 8.18(1H, dd, J=8.6, 2.3 Hz), 8.35(1H, d, J=2.3 Hz)

Example 25b Synthesis of 2-cyano-2-(2-ethyl-5-nitrophenyl)indane

To a mixture of the compound (3.0 g) obtained in Example 25a, α,α′-dichloro-o-xylene (4.15 g) and dimethyl sulfoxide (200 ml), potassium t-butoxide (3.55 g) was added and after stirring the resulting mixture at room temperature for 3 h, ethyl acetate and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (1.36 g) (yield, 29%).

¹H-NMR(CDCl₃) δ: 1.45(3H, t. J=7.6 Hz), 3.11(2H, q, J=7.6 Hz), 3.61(2H, d, J=15.5 Hz), 3.91(2H, d, J=15.5 Hz), 7.25-7.33(4H, m), 7.53(1H, d, J=9.2 Hz), 8.12-8.16(2H, m)

Example 25c Synthesis of 2-(2-ethyl-5-nitrophenyl)-2-indaneamide

To a mixture of the compound (1.16 g) obtained in Example 25b and acetic acid (10 ml), water (2 ml) and concentrated sulfuric acid (20 ml) were added sequentially. The reaction mixture was heated under reflux for 13 h, cooled, put into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (870 mg) (yield, 71%).

¹H-NMR(CDCl₃) δ: 1.35(3H, t, J=7.6 Hz), 2.82(2H, q, J=7.6 Hz), 3.36(2H, d, J=15.9 Hz), 3.95(2H, d, J=15.9 Hz), 5.13(1H, brs), 5.43(1H, brs), 7.15-7.25(4H, m), 7.49(1H, d, J=8.3 Hz), 8.08(1H, dd, J=8.3, 2.3 Hz), 8.17(1H, d, J=2.3 Hz)

Example 25d Synthesis of 2-(t-butoxycarbonylamino)-2-(2-ethyl-5-nitrophenyl)indane

To a mixture of the compound (815 mg) obtained in Example 25c and t-butanol (12 ml), lead tetracetate (1.40 g) was added. The reaction mixture was heated under reflux for 3 h, cooled and, after adding water, subjected to extraction with ethyl acetate-ethylene glycol. The organic layer was washed with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform) to give the titled compound (620 mg) (yield, 62%).

¹H-NMR(CDCl₃) δ: 1.30(3H, t, J=7.6 Hz), 1.31(9H, s), 2.93(2H, q, J=7.6 Hz), 3.55(2H, d, J=15.9 Hz), 3.63(2H, d, J=15.9 Hz), 5.18(1H, s), 7.20-7.29(4H, m), 7.40(1H, d, J=8.6 Hz), 8.05(1H, dd, J=8.6, 2.3 Hz), 8.32(2H, d, J=2.3 Hz)

Example 25e Synthesis of 2-(5-amino-2-ethylphenyl)-2-(t-butoxycarbonylamino)indane

Using the compound obtained in Example 25d as a starting material, the procedure of Example 3 was repeated to give the titled compound (yield, 97%).

¹H-NMR(CDCl₃) δ: 1.23(3H, t, J=7.6 Hz), 1.30(9H, s), 2.74(2H, q, J=7.6 Hz), 3.48-3.67(6H, m), 5.02(1H, s), 6.56(1H, dd, J=8.3, 2.3 Hz), 6.74(1H, d, J=2.3 Hz), 7.03(1H, d, J=8.3 Hz), 7.15-7.24(4H, m)

Example 417e Synthesis of N-(3-amino-2-ethoxyphenylmethyl)iminodicarboxylic acid di-t-butyl ester Example 417a Synthesis of 2-ethoxy-3-nitrobenzoic acid ethyl ester

To a mixture of 3-nitrosalicylic acid (5.0 g), ethyl iodide (11 ml) and dimethylformamide (200 ml), potassium carbonate (9.4 g) was added. The reaction mixture was stirred at 60° C. for 4.5 h and, after adding water, subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:1) to give 5.66 g of the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 8.01(1H, dd, J=7.9, 1.7 Hz), 7.89(1H, dd, J=7.9, 1.7 Hz), 7.26(1H, dd, J=7.9, 7.9 Hz), 4.42(2H, q, J=7.3 Hz), 4.18(2H, q, J=6.9 Hz), 1.43(3H, t, J=6.9 Hz), 1.42(3H, t, J=7.3 Hz)

Example 417b Synthesis of 2-ethyoxy-3-nitrobenzyl alcohol

To a mixture of the compound (117 mg) obtained in Example 417a, tetrahydrofuran (5 ml) and methanol (2 ml), lithium borohydride (10.7 mg) was added. The reaction mixture was stirred at room temperature for 15 h, and, after addition of water, concentrated under reduced pressure. To the resulting residue, 2 N HCl was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:2) to give the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 7.77(1H, d, J=7.9 Hz), 7.67(1H, d, J=7.3 Hz), 7.22(1H, dd, J=7.9, 7.3 Hz), 4.80(2H, s), 4.08(2H, q, J=6.8 Hz), 2.10(1H, brs), 1.44(3H, t, J=6.8 Hz)

Example 417c Synthesis of 2-ethoxy-3-nitrobenzyl bromide

To a mixture of the compound (3.13 g) obtained in Example 417b, carbon tetrabromide (5.26 g) and methylene chloride (100 ml), triphenylphosphine (4.16 g) was added under ice cooling. The reaction mixture was stirred under ice cooling for 30 min and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate: n-hexane=1:9) to give 3.59 g of the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 7.78(1H, dd, J=7.9, 1.7 Hz), 7.65(1H, dd, J=7.6, 1.7 Hz), 7.20(1H, dd, J=7.9, 7.6 Hz), 4.57(2H, s), 4.17(2H, q, J=6.9 Hz), 1.49(3H, t, J=6.9 Hz)

Example 417d Synthesis of N-(2-ethoxy-3-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

A mixture of iminodicarboxylic acid di-t-butyl ester (3.23 g), dimethylformamide (50 ml) and sodium hydride (0.57 g) was stirred under ice cooling for 1 h and then a mixture of the compound (3.51 g) obtained in Example 417c and dimethylformamide (20 ml) was added under ice cooling. The reaction mixture was stirred at room temperature for 14 h and, after addition of 2 N HCl, subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:9) to give 5.09 g of the titled compound (yield, 95%).

¹H-NMR(CDCl₃) δ: 7.72(1H, dd, J=7.9, 1.3 Hz), 7.38(1H, dd, J=7.3, 1.3 Hz), 7.17(1H, dd, J=7.9, 7.3 Hz), 4.91(2H, s), 4.06(2H, q, J=6.9 Hz), 1.45(18H, s), 1.44(3H, t, J=6.9 Hz)

Example 417e Synthesis of N-(3-amino-2-ethoxyphenylmethyl)iminodicarboxylic acid di-t-butyl ester

To a mixture of the compound (5.09 g) obtained in Example 417d, nickel (II) chloride hexahydrate (61 mg) and methanol (130 ml), sodium borohydride (1.46 g) was added. The reaction mixture was stirred at room temperature for 20 min and, after addition of 2 N HCl, adjusted to pH 8 with a saturated aqueous sodium hydrogencarbonate solution and then concentrated under reduced pressure. To the resulting residue, water was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:4) to give the titled compound (yield, 85%).

¹H-NMR(CDCl₃) δ: 6.86(1H, dd, J=7.9, 7.6 Hz), 6.63(1H, dd, J=7.6, 1.0 Hz), 6.53(1H, dd, J=7.9, 1.0 Hz), 4.85(2H, s), 3.90(2H, q, J=6.9 Hz), 3.74(2H, brs), 1.43(18H, s), 1.41(3H, t, J=6.9 Hz)

Example 500b Synthesis of N-(5-amino-2-(pyrazole-1-yl)phenylmethyl)carbamic acid t-butyl ester Example 500a Synthesis of N-(5-nitro-2-(pyrazole-1-yl)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

To a mixture of pyrazole (1.0 g) and dimethylsulfoxide (50 ml), sodium hydride (0.54 g) was added under ice cooling. The reaction mixture was stirred under ice cooling for 1 h and then a solution of N-(2-fluoro-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester (5.0 g) in dimethyl sulfoxide (50 ml) was added. The reaction mixture was stirred at room temperature for 15 h and, after addition of water, subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:4) to give the titled compound (yield, 73%).

¹H-NMR(CDCl₃) δ: 8.22-8.19(2H, m), 7.79-7.78(2H, m), 7.50(1H, d, J=9.6 Hz), 6.53(1H, dd, J=2.3, 2.0 Hz), 4.95(2H, s), 1.46(18H, s)

Example 500b Synthesis of N-(5-amino-2-(pyrazole-1-yl)phenylmethyl)carbamic acid t-butyl ester

To a mixture of the compound (4.15 g) obtained in Example 500a, nickel (II) chloride hexahydrate (0.183 g) and methanol (300 ml), sodium borohydride (2.43 g) was added. The reaction mixture was stirred at room temperature for 55 min; thereafter, 2 N HCl was added to render the reaction solution acidic and then a saturated aqueous sodium hydrogencarbonate solution was added to render the reaction solution basic; subsequently, the reaction mixture was concentrated under reduced pressure. To the resulting residue, water was added and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate/n-hexane to give the titled compound (yield, 89%).

¹H-NMR(CDCl₃) δ: 7.69(1H, d, J=1.3 Hz), 7.57(1H, d, J=2.0 Hz), 7.06(1H, d, J=8.3 Hz), 6.86-6.83(1H, m), 6.60(1H, dd, J=8.3, 2.3 Hz), 6.41(1H, dd, J=2.0, 1.3 Hz), 5.62(1H, brs), 4.01(2H, d, J=6.6 Hz), 3.82(2H, brs), 1.43(9H, s)

Example 519e Synthesis of 3-(t-butoxycarbonylaminomethyl)-4-chloro-2-ethoxyaniline Example 519a Synthesis of 5-bromo-4-chloro-2-fluoronitrobenzene

To a mixture of 4-chloro-2-fluoronitrobenzene (1.00 g), silver sulfate (1.95 g) and concentrated sulfuric acid (5 ml), bromine (0.32 ml) was added under ice cooling and the resulting mixture was stirred at 0° C. for 30 min, then at room temperature for 1 h. The reaction mixture was put into ice water and subjected to extraction with ether. The organic layer was washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution sequentially, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 1.38 g of the titled compound (yield, 95%).

¹H-NMR(CDCl₃) δ: 7.47(1H, d, J=9.9 Hz), 8.37(1H, d, J=7.3 Hz)

Example 519b Synthesis of 5-bromo-4-chloro-2-fluoro-3-(trifluoromethylcarbonylaminomethyl)nitrobenzene

A mixture of the compound (204 mg) obtained in Example 519a, N-hydroxymethyl-2,2,2-trifluoroacetamide (115 mg) and 10% fuming sulfuric acid (1.6 ml) was stirred at 80° C. for 10 h. The reaction mixture was cooled, put into ice water and subjected to extraction with ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution sequentially, then dried with anhydrous sodium sulfate and concentrated under reduced pressure.

The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:3) to give 85.1 mg of the titled compound (yield, 28%).

¹H-NMR(CDCl₃) δ: 4.86(2H, d, J=4.0 Hz), 6.73(1H, brt), 8.39(1H, d, J=7.3 Hz)

Example 519c Synthesis of 5-bromo-3-(t-butoxycarbonylaminomethyl)-4-chloro-2-fluoronitrobenzene

A mixture of the compound (601 mg) obtained in Example 519b, concentrated sulfuric acid (3 ml) and methanol (12 ml) was heated under reflux for 1 h. The reaction mixture was concentrated under reduced pressure and, after being rendered basic by addition of a 2 N aqueous sodium hydroxide solution, it was subjected to extraction with methylene chloride (20 ml). To the organic layer, di-t-butyl dicarbonate (414 mg) and a 2 N aqueous sodium hydroxide solution (10 ml) were added at room temperature and the resulting mixture was stirred at room temperature for 2 h. The organic layer was washed with water and a saturated aqueous sodium chloride solution sequentially, then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform) to give 402 mg of the titled compound (yield, 66%).

¹H-NMR(CDCl₃) δ: 1.44(9H, s), 4.57-4.66(2H, m), 5.01(1H, brt), 8.31(1H, d, J=7.6 Hz)

Example 519d Synthesis of 5-bromo-3-(t-butoxycarbonylaminomethyl)-4-chloro-2-ethoxynitrobenzene

To a mixture of the compound (200 mg) obtained in Example 519c, ethanol (36 μl) and tetrahydrofuran (5 ml), sodium hydride (content, 60%; 25 mg) was added under ice cooling. The reaction mixture was stirred at 0° C. for 2 h and then water and ether were added. The organic layer was washed with water and a saturated aqueous sodium chloride solution sequentially, then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:4) to give 197 mg of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.45(9H, s), 1.47(3H, t, J=6.9 Hz), 4.08(2H, q, J=6.9 Hz), 4.62(2H, d, J=5.9 Hz), 4.93(1H, brt), 8.10(1H, s)

Example 519e Synthesis of 3-(t-butoxycarbonylaminomethyl)-4-chloro-2-ethoxyaniline

Using the compound obtained in Example 519d as a starting material, the procedure of Example 3 was repeated to give the titled compound (86%).

¹H-NMR(DCDl₃) δ: 1.44(3H, t, J=7.3 Hz), 1.45(9H, s), 3.78(2H, brs), 3.92(2H, q, J=7.3 Hz), 4.47(2H, d, J=5.3 Hz), 4.91(1H, brt), 6.63(1H, d, J=8.3 Hz), 6.94(1H, d, J=8.3 Hz)

Example 520d Synthesis of 3-(t-butoxycarbonylaminomethyl)-2-ethoxy-6-methylaniline Example 520a Synthesis of 3-methyl-6-nitro-2-(trifluoromethylcarbonylaminomethyl)phenol

Using 5-methyl-2-nitrophenol as a starting material, the procedure of Example 545b was repeated to give the titled compound (16%).

¹H-NMR(CDCl₃) δ: 2.57(3H, s), 4.67(2H, d, J=6.3 Hz), 6.89(1H, d, J=8.6 Hz), 7.00(1H, brs), 8.00(1H, d, J=8.6 Hz), 11.23(1H, s)

Example 520b Synthesis of 2-(t-butoxycarbonylaminomethyl)-4-methyl-6-nitrophenol

A mixture of the compound (100 mg) obtained in Example 520a, potassium carbonate (99.4 mg), water (1.0 ml) and methanol (6.0 ml) was stirred at room temperature for 3 h and then di-t-butyl dicarbonate (157 mg) was added. The reaction mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. To the resulting residue, a saturated aqueous sodium chloride solution was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=3:17) to give the titled compound (yield, 70%).

¹H-NMR(CDCl₃) δ: 1.43(9H,s), 2.55(3H, s), 4.44(2H, d, J=6.3 Hz), 5.17(1H, brs), 6.82(1H, d, J=8.6 Hz), 7.94(1H, d, J=8.6 Hz), 11.11(1H, s)

Example 520c Synthesis of 3-(t-butoxycarbonylaminomethyl)-2-ethoxy-4-methylnitrobenzene

A mixture of the compound (350 mg) obtained in Example 520b, cesium carbonate (404 mg), dimethylformamide (15 ml) and ethyl iodide (0.4 ml) was stirred at 60° C. for 2 h. To the reaction mixture, ethyl acetate and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=2:8) to give the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.44(9H, s), 1.48(3H, t, J=6.9 Hz), 2.49(3H, s), 4.03(2H, q, J=6.9 Hz), 4.41(2H, d, J=5.6 Hz), 4.86(1H, brs), 7.03(1H, d, J=8.6 Hz), 7.72(1H, d, J=8.6 Hz)

Example 520d Synthesis of 3-(t-butoxycarbonylaminomethyl)-2-ethoxy-4-methylaniline

Using the compound obtained in Example 520c as a starting material, the procedure of Example 3 was repeated to give the titled compound (92%).

¹H-NMR(CDCl₃) δ: 1.43(3H, t, J=6.9 Hz), 1.44(9H, s), 2.26(3H, s), 3.61(2H, brs), 3.89(2H, q, J=6.9 Hz), 4.34(2H, d, J=5.3 Hz), 4.70(1H, brs), 6.61(1H, d, J=7.9 Hz), 6.75(1H, d, J=7.9 Hz)

Example 538e Synthesis of N-(3-amino-2-(n-propoxy)phenylmethyl)iminodicarboxylic acid di-t-butyl ester Example 538a Synthesis of 3-nitro-2-(n-propoxy)benzoic acid n-propyl ester

Using 3-nitrosalicylic acid as a starting material and also using n-propyl iodide as a reagent, the procedure of Example 417a was repeated to give the titled compound (yield, 29%).

¹H-NMR(CDCl₃) δ: 7.98(1H, dd, J=7.6, 1.7 Hz), 7,87(1H, dd, J=7.9, 1.7 Hz), 7.24(1H, dd, J=7.9, 7.6 Hz), 4.31(2H, t, J=6.9 Hz), 4.05(2H, t, J=6.9 Hz), 1.90-1.71(4H, m), 1.08-0.97(6H, m)

Example 538b Synthesis of 3-nitro-2-(n-propoxy)benzyl alcohol

Using the compound obtained in Example 538a as a starting material, the procedure of Example 417b was repeated to give the titled compound (yield, 70%).

¹H-NMR(CDCl₃) δ: 7.76(1H, dd, J=8.3, 1.3 Hz), 7.68(1H, dd, J=7.3, 1.3 Hz), 7.21(1H, dd, J=8.3, 7.3 Hz), 4.80(2H, s), 3.96(2H, t, J=6.9 Hz), 2.13(1H, brs), 1.91-1.77(2H, m), 1.04(3H, t, J=7.3 Hz)

Example 538c Synthesis of 3-nitro-2-(n-propoxy)benzyl bromide

Using the compound obtained in Example 538b as a starting material, the procedure of Example 417c was repeated to give the titled compound (yield, 95%).

¹H-NMR(CDCl₃) δ: 7.77(1H, dd, J=7.9, 1.3 Hz), 7.64(1H, dd, J=7.9, 1.3 Hz), 7.19(1H, dd, J=7.9, 7.9 Hz), 4.57(2H, s), 4.05(2H, t, J=6.6 Hz), 1.96-1.83(2H, m), 1.07(3H, t, J=7.3 Hz)

Example 538d Synthesis of N-(3-nitro-2-(n-propoxy)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 538c as a starting material, the procedure of Example 417d was repeated to give the titled compound (yield, 62%).

¹H-NMR(CDCl₃) δ: 7.70(1H, dd, J=7.9, 1.3 Hz), 7.37(1H, dd, J=7.9, 1.3 Hz), 7.16(1H, dd, J=7.9, 7.9 Hz), 4.91(2H, s), 3.94(2H, t, J=6.6 Hz), 1.91-1,80(2H, m), 1.45(18H, s), 1.05(3H, t, J=7.3 Hz)

Example 538e Synthesis of N-(3-amino-2-(n-propoxy)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 538d as a starting material, the procedure of Example 417e was repeated to give the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 6.86(1H, dd, J=7.9, 7.6 Hz), 6.63(1H, d, J=7.9 Hz), 6.52(1H, d, J=7.6 Hz), 4.85(2H, s), 3.78(2H, t, J=6.6 Hz), 3.74(2H, brs), 1.89-1.75(2H, m), 1.43(18H, s), 1.07(3H, t, J=7.3 Hz)

Example 542a Synthesis of N-(3-amino-2-(i-propoxy)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using 3-nitrosalicylic acid as a staring material and also using i-propyl iodide as a reagent, the procedures of Examples 417a-417e were repeated to give the titled compound.

¹H-NMR(CDCl₃) δ: 6.85(1H, dd, J=7.9, 7.6 Hz), 6.62(1H, d, J=7.6 Hz), 6.53(1H, d, J=7.9 Hz), 4.83(2H, s), 4.26-4.15(1H, m), 3.69(2H, brs), 1.42 (18H, s), 1.31(6H, d, J=6.3 Hz)

Test Examples Test Example 1

Compounds of the invention were evaluated for their inhibitory effect on the presently known three NOS isoforms.

Crude enzymes of the respective NOS isoforms were prepared by the following procedures (Nagafuji et al., Neuroreport 6, 1541-1545, 1995).

The crude enzyme of nNOS was prepared by the following procedure. Normal untreated male Sprague Dawley (SD) rats (body weight, 300-400 g) were decapitated; the whole brain was immediately taken out from each animal and the cerebral cortex was separated on ice. Then, 5 volumes of 50 mM Tris-HCl containing 1 mM DTT (pH 7.4) was added and the mixture was homogenized for 3 min and centrifuged at 1,000×g for 10 min. The resulting supernatant was further centrifuged at 100,000×g for 60 min and a soluble cytosolic fraction of the finally obtained supernatant was used as the crude enzyme of nNOS.

The crude enzyme of iNOS was prepared by the following procedure. Rats were administered LPS (10 mg/kg) intraperitoneally and, 6 h later, perfused in a transcardiac manner with physiological saline containing 10 U/ml of heparin; thereafter, lungs were taken out. Subsequently, 5 volumes of 50 mM Tris-HCl containing 1 mM DTT (pH 7.4) was added and the mixture was homogenized for 3 min, followed by centrifugation of the homogenate at 1,000×g for 10 min. The resulting supernatant was centrifuged at 100,000×g for 60 min and a soluble cytosolic fraction of the finally obtained supernatant was used as the crude enzyme of iNOS.

The crude enzyme of eNOS was prepared by the following procedure. Cow pulmonary arterial endothelium cells (CPAE) were cultured in a MEM medium containing 20% FBS. Several days later, the cells were detached from the flask using a 0.25% trypsin solution containing 1 mM EDTA and, after addition of a suitable amount of FBS, centrifuged at 1,000 rpm for 10 min. A suitable amount of Ca- and Mg-free phosphate buffer (pH 7.4) was added to the precipitating cells and they were centrifuged at 1,000 rpm for 10 min. The same step was repeated to wash the cells which, upon addition of 50 mM Tris-HCl (pH 7.4) containing 1% Triton X-100 and 1 mM DTT, were left to stand in ice for 1 h. Subsequently, the mixture was homogenized for 3 min and kept in ice for 30 min with occasional stirring. Finally, the mixture was centrifuged at 100,000×g for 60 min and the resulting supernatant was used as the crude enzyme of eNOS.

The method of measuring NOS activity was basically the same as already reported by the present inventors and consisted of determining quantitatively the conversion of a substrate L-[³H]arginine to a reaction product L-[³H] citrulline (Nagafuji et al., in Brain Edema IX (Ito et al, eds.) 60, pp. 285-288, 1994; Nagafuji et al., Neuroreport 6, 1541-1545, 1995)

The reaction solution consisted of 100 nM L-[³H] arginine, a prepared crude NOS enzyme sample (10-30 μg/ml protein), 1.25 mM CaCl₂, 1 mM EDTA, 10 μg/ml calmodulin, 1 mM NADPH, 100 μM tetrahydrobiopterine, 10 μM FAD, 10 μM FMN and 50 mM Tris-HCl (pH 7.4), to which one of the compounds of the invention or one of the control compounds was added.

The reaction was started by addition of L-[³H] arginine. After incubation at 37° C. for 10 min, the reaction was terminated by addition of 2 ml of 50 mM Tris-HCl (pH 5.5) containing 1 mM EDTA and placing the mixture on ice. The reaction solution was passed through a cation-exchange resin column (Dowex AG50WX-8, Na⁺ form, 3.2 ml) to separate the reaction product L-[³H] citrulline from the unreacted residual substrate L-[³H] arginine. The eluate was combined with another eluate resulting from the passage of a given amount of distilled water through the column and put into a minivial for recovery of L-[³H] citrulline. Thereafter, a scintillation fluid was added and the contained radioactivity was measured with a liquid scintillation counter to determine the amount of L-[³H] citrulline.

The activity of nNOS or eNOS was determined by subtracting the activity detected in the absence of CaCl₂ and calmodulin from the activity detected in the presence of CaCl₂ and calmodulin. The activity of iNOS was detected in the absence of CaCl₂ and calmodulin. The protein concentration of each crude enzyme sample was determined with a micro-assay kit of Bio Rad Co. Each Experiment was conducted in a duplicate.

Table 81 lists the mean values of IC₅₀ (the concentration necessary to inhibit 50% activity) of all test compounds against each NOS isoform. The table also lists the ratios of IC₅₀ values to each other as an index of selectivity.

TABLE 81 Inhibitory Action and Selectivity of Test Compounds against Three NOS Isoforms Example No. Inhibitory action Selectivity or Control IC₅₀ (nM) iNOS/ eNOS/ eNOS/ Compound nNOS iNOS eNOS nNOS nNOS iNOS  18 22.6  916.7 322.4 41 14 0.14  52 79.8 N.D. 1476.7 — 19 —  53 86.1 N.D. 6624.3 — 77 —  57 70.8 N.D. 947.4 — 13 —  61 126.0 N.D. 1614.9 — 13 151 126.2 N.D. 679.3 — 5 — 153 29.8 N.D. 586.1 — 20 — 458 20.8 N.D. 403.1 — 19 — 460 111.7 N.D. 1244.3 — 11 — 462 16.4 N.D. 257.2 — 16 — 465 31.2 N.D. 1000.0 — 32 — 466 35.5 N.D. 421.0 — 12 — 467 19.6 N.D. 274.6 — 14 — 468 56.3 N.D. 2481.0 — 44 — 469 40.0 N.D. 994.0 — 25 — 478 61.6 N.D. 447.5 — 7 — 479 66.9 N.D. 802.0 — 12 — 481 78.1 N.D. 1984.5 — 25 — 482 50.5 N.D. 1348.6 — 27 — 483 65.4 N.D. 711.0 — 11 — 484 69.2 N.D. 1264.2 — 18 — 485 54.4 1774.9 2882.4 32 53 1.6  488 39.9 N.D. 297.9 — 8 — 489 22.1 N.D. N.D. — — — 490 18.1 N.D. 347.5 — 19 — 491 45.8 N.D. 1768.0 — 39 — 506 29.1 N.D. 1292.7 — 45 — 521 19.5 N.D. 485.2 — 25 — 522 19.7 N.D. 398.4 — 20 — 541 25.9 N.D. 712.6 — 28 — 543 12.5 N.D. 249.8 — 20 — L-NA 16.9 3464.3 68.2 205.0 4.0 0.02 Notes: Symbol “N.D.” means “not determined”, and “—” means “uncalculable”

INDUSTRIAL APPLICABILITY

The compounds of the present invention exhibit an outstanding nNOS or iNOS inhibiting activity and are useful as therapeutics of cerebrovascular diseases [cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction (atherothrombotic infarction, lacunar infarction and cardiogenic embolism), transient ischemic attack and cerebral edema], traumatic brain injury, spinal injury, pains [headache (migraine, tension headache, cluster headache and chronic paroxysmal headache)], Parkinson's disease, Alzheimer's disease, seizure, morphine tolerance or dependence, septic shock, chronic rheumatoid arthritis, osteoarthritis, viral or nonviral infections and diabetes mellitus. 

What is claimed is:
 1. A compound represented by formula (1), or a tautomer, stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof

where R₁ and R₂, which may be the same or different, are each a hydrogen atom, an optionally substituted lower alkyl group, an acyl group or a lower alkoxycarbonyl group, or R₁ and R₂ may combine together to form a 3- to 8-membered ring; R₃ and R₄, which may be the same or different, are each a hydrogen atom, an optionally substituted lower alkyl group, or R₃ and R₄ may combine together to form a monocyclic or fused ring having 3-10 carbon atoms; R₅ is a hydrogen atom, a lower alkyl group, an acyl group or a lower alkoxycarbonyl group; X₁, X₂, X₃, and X₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl, group, an optionally substituted lower alkyl group, a lower alkenyl group, a lower alkynyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkylthio group, a phenyl group optionally substituted by a halogen atom and/or a lower alkyl group, NX₅X₆ or C(═O)X₇; where X₅ and X₆, which may be the same or different, are each a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted lower alkoxycarbonyl group, or X₅ and X₆ may combine together to form a 3- to 8-membered ring; X₇ is a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, or NX₈X₉; where X₈ and X₉, which may be the same or different, are each a hydrogen atom, an optionally substituted lower alkyl group, or X₈ and X₉ may combine together to form a 3- to 8-membered ring; A is a substituted benzene ring or a 5- or 6-membered aromatic hetero ring which is optionally substituted and which contains at least one nitrogen atom as a hetero atom; n and m are each an integer of 0 or 1, with the proviso that when A is a substituted benzene ring the substituent(s) of which is (are) a nitro group, an amino group or a carboxyl group, either of R₁ or R₂ is a hydrogen atom, and that when A is a substituted benzene, the substituent is not a di-(3-chloroethyl)amino group, and that when A is a pyridine ring substituted by a nitro group, none of X₁, X₂, X₃ and X₄ are a hydroxyl group.
 2. The compound according to claim 1 wherein X₁, X₂, X₃ and X₄, which may be the same or different, are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, an optionally substituted lower alkyl group, a lower alkenyl group, a lower alkynyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkylthio group, a phenyl group optionally substituted by a halogen atom and/or a lower alkyl group, NX₅X₆ or C(═O)X₇; and A is a substituted benzene or pyridine ring.
 3. The compound of claim 1 wherein: A is a 5- or 6-membered aromatic hetero ring which is optionally substituted and which contains at least one nitrogen atom as a hetero atom (exclusive of an optionally substituted pyridine ring).
 4. The compound of claim 1 wherein: R₁ is a hydrogen atom; R₂ is a hydrogen atom, a lower alkyl group, an acyl group or a lower alkoxycarbonyl group; and A is a substituted benzene ring.
 5. The compound of claim 2 wherein: A is an optionally substituted pyridine ring.
 6. The compound claim 1 wherein: R₁ and R₂ are each a hydrogen atom; R₅ is a hydrogen atom; X₁, X₂, X₃ and X₄ which may be the same or different are each a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group or NX₅X₆; and A is a substituted benzene ring, an optionally substituted pyridine ring, an optionally substituted pyrimidine ring, an optionally substituted oxazole ring, or an optionally substituted thiazole ring.
 7. The compound of claim 6 wherein: A is a substituted benzene ring or an optionally substituted pyridine ring.
 8. The compound of claim 1 wherein: R₃ and R₄ which may be the same or different are each a hydrogen atom or a lower alkyl group, or R₃ and R₄ may combine together to form a monocyclic ring having 3-10 carbon atoms.
 9. The compound of claim 1 wherein: X₁, X₂, X₃, and X₄ which may be the same or different are each a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group optionally substituted by a phenyl group or NX₅X₆; where X₅ and X₆ which may be the same or different are each a hydrogen atom, a lower alkyl group optionally substituted by a phenyl group or an acyl group, or X₅ and X₆ may combine together to form a 3- to 8-membered ring.
 10. The compound of claim 6 wherein: A is a substituted benzene ring or a substituted pyridine ring, with the optional substituent being a nitro group, a lower alkoxy group, a lower alkyl group or a lower alkylthio group.
 11. The compound of claim 1 wherein: X₁, X₂, X₃, or X₄ which may be the same or different are each a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or NX₅X₆; where X₅ and X₆, which may be the same or different, are each a hydrogen atom, a lower alkyl group or an acyl group, or X₅ and X₆ may combine together to form a 3- to 8-membered ring.
 12. The compound of claim 1 wherein: m and n are each 0; and the substituents other than X₁, X₂, X₃ and X₄ are meta-substituted on the benzene ring.
 13. The compound of claim 1 wherein: m+n=1; and the substituents other than X₁, X₂, X₃ and X₄ are ortho- or para-substituted on the benzene ring.
 14. The compound of claim 1 selected from the group consisting of: 2-(3-aminomethylphenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethylphenylamino)-6-methyl-3-nitropyridine, 2-(3-aminomethylphenylamino)-6-ethyl-3-nitropyridine, 2-(3-aminomethylphenylamino)-6-ethoxy-3-nitropyridine, 2-(3-aminomethylphenylamino)-6-methylthio-3-nitropyridine, 2-(3-aminomethylphenylamino)-6-methyl-3-nitrobenzene, 2-(3-aminomethylphenylamino)-6-methoxy-3-nitrobenzene, 2-(3-aminomethyl-2-methylphenylamino)-6-methoxy-3-nitropyridine, 2-(4-aminoethylphenylamino)-6-methoxy-3-nitropyridine, 2-(3-(1-amino-1-methylethyl)phenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethyl-2-methoxyphenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethyl-4-chlorophenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethyl-4-fluorophenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethyl-2-ethoxyphenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethyl-2-chlorophenylamino)-6-methoxy-3-nitropyridine, 2-(3-aminomethylphenylamino)-4-methylpyridine, 2-(3-(1-amino-1-methylethyl)-phenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-methylphenylamino)-4-methylpyridine, 2-(3-aminomethyl-4-ethylphenylamino)-4-methylpyridine, 2-(3-aminomethyl-4-ethoxyphenylamino)-4-methylpyridine, 2-(2aminoethylphenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-chlorophenylamino)-4-methylpyridine, 2-(3-(1-amino-cyclobutyl)phenylamino)-4-methylpyridine, 2-(4-aminoethylphenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-ethoxyphenylamino)-4-methylpyridine, 2-(3-aminomethyl-4-chlorophenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-(n-propoxy)phenylamino)-4-methylpyridine, 2-(3-aminomethyl-4-chloro-2-ethoxyphenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-ethoxy-4-methylphenylamino)-4-methylpyridine, 2-(3-aminomethyl-2-methoxyphenylamino)-4-methylpyridine, and 2-(3-aminomethyl-2-(i-propoxy)phenylamino)-4-methylpyridine.
 15. A nNOS inhibitor composition comprising as an active ingredient the compound of claim 1 in a pharmaceutically effective amount, and a pharmaceutically acceptable adjuvant.
 16. A method for the treatment of a cerebrovascular disease comprising administering to a patient in need thereof an amount sufficient for said therapy of the compound of claim
 1. 17. The method of claim 16, wherein said patient is one suffering from cerebral hemorrhage.
 18. The method according to claim 16, wherein the type of cerebrovascular disease is subarachnoid hemorrhage.
 19. The method according to claim 16, wherein the type of cerebrovascular disease is cerebral infarction.
 20. The method according to claim 19, wherein the subtype of cerebral infarction is atherothrombotic infarction.
 21. The method according to claim 19, wherein the subtype of cerebral infarction is lacunar infarction.
 22. The method according to claim 19, wherein the subtype of cerebral infarction is cardiogenic embolism.
 23. The method according to claim 19, wherein the type of cerebrovascular disease is transient ischemic attack.
 24. The method according to claim 16, wherein the type of cerebrovascular disease is cerebral edema.
 25. A method for the treatment of a traumatic brain injury comprising administering to a patient in need thereof an amount sufficient for said therapy of the compound of claim
 1. 26. A method for the treatment of a spinal injury comprising administering to a patient in need thereof an amount sufficient for said therapy of the compound of claim
 1. 27. A method for the treatment of pain in a patient in need of said therapy, comprising administering to said patient an analgesic-effective amount of the compound of claim
 1. 28. The method according to 27 wherein said patient is suffering from headache.
 29. The method according to claim 28, wherein said headache is a migraine headache.
 30. The method according to claim 28, wherein said headache is a tension headache.
 31. The therapeutic according to claim 28, wherein said headache is a cluster headache or chronic paroxysmal headache.
 32. A method for the treatment of Parkinson's disease comprising administering to a patient suffering from Parkinson's disease an amount sufficient for said treatment of the compound of claim
 1. 33. A method for the treatment of Alzheimer's disease comprising administering to a patient suffering from Parkinson's disease an amount sufficient for said treatment of the compound of claim
 1. 34. A method for the treatment of seizure disorder, comprising administering to a patient in need thereof an effective amount for seizure control or seizure diminution of the compound of claim
 1. 35. A method for the treatment of morphine tolerance or dependents, comprising administering to a patient in need thereof an amount sufficient for said therapy of the compound of claim
 1. 36. A method for the treatment of septic shock comprising administering to a patient in need thereof an amount effective for said treatment of the compound of claim
 1. 37. A method for the treatment of chronic rheumatoid arthritis comprising administering to a patient in need of said therapy an amount sufficient for said treatment of the compound of claim
 1. 38. A method for the treatment of osteoarthritis comprising administering to a patient in need of said therapy an effective amount for said treatment of the compound of claim
 1. 39. A method for the treatment of an infection comprising administering to a patient in need of said therapy an amount sufficient for said therapy of the compound of claim
 1. 40. The method of claim 39 wherein said patient is suffering from a viral infection.
 41. A method for the treatment of diabetes mellitus comprising administering to a patient in need of said therapy an amount effective for said treatment of the compound of claim
 1. 42. A process for producing a compound according to claim 1 by the reaction pathway (A):

wherein; R₅ is a hydrogen atom or an optionally substituted lower alkyl group; and L is a leaving group.
 43. A process for producing a compound according to claim 1 by the reaction pathway (B):

wherein R₅ is a hydrogen atom or an optionally substituted lower alkyl group; and L is a leaving group. 